Developmental Neurotoxicity of Ketamine in Pediatric Clinical Use

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Toxicology Letters 220 (2013) 53–60

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Mini review

Developmental neurotoxicity of ketamine in pediatric clinical use

a,b,∗ b,c

Chaoxuan Dong , K.J.S. Anand

Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States

Departments of Pediatrics, Anesthesiology, Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38103, United States

Pediatric Intensive Care Unit, Department of Pediatrics, Le Bonheur Children’s Hospital, Memphis, TN 38105, United States

h i g h l i g h t s

•

History and pharmacology of ketamine.

•

Ketamine induces neuronal cell death in developing brains.

•

Ketamine alters the neurogenesis of early developing brains.

•

Current studies on the developmental neurotoxicity of ketamine in pediatric clinical use.

a r t i c l e i n f o a b s t r a c t

Article history: Ketamine is widely used as an anesthetic, analgesic, and sedative in pediatric clinical practice and it is

Received 2 January 2013

also listed as an illicit drug by most countries. Recent in vivo and in vitro animal studies have conﬁrmed

Received in revised form 21 March 2013

that ketamine can induce neuronal cell death in the immature brain, resulting from widespread neuronal

Accepted 22 March 2013

apoptosis. These effects can disturb normal development further altering the structure and functions of

Available online xxx

the brain. Our recent studies further indicate that ketamine can alter neurogenesis from neural stem

progenitor cells in the developing brain. Taken together, these ﬁndings identify a novel complication

Keywords:

associated with ketamine use in premature infants, term newborns, and pregnant women. Recent data on

Ketamine

the developmental neurotoxicity of ketamine are reviewed with proposed future directions for evaluating

NMDA receptors

the safety of ketamine in these patient populations.

Neural stem progenitor cells

Contents

1. Ketamine ...... 54

2. Pharmacology ...... 54

3. Clinical use and complications ...... 54

4. Ketamine induces cell death in developing brains ...... 55

5. Ketamine alters the neurogenesis of early developing brains ...... 55

5.1. Proliferation ...... 56

5.2. Differentiation ...... 57

6. Conclusions ...... 57

7. Future directions ...... 57

Conﬂict of interest statement ...... 58

References ...... 58

∗

Corresponding author at: 262 Danny Thomas Pl. MS 1000, Memphis, TN 38105, United States. Tel.: +1 901 834 6612; fax: +1 901 595 5715.

E-mail address: [email protected] (C. Dong).

54 C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60

1. Ketamine 2009; Seeman et al., 2009; Seeman and Lasaga, 2005). Effects of

ketamine on dopaminergic receptors may support the theory of

Ketamine was synthesized as a substitute for phencyclidine glutamatergic contributions to schizophrenia (Gilmour et al., 2012).

(PCP) in 1962, and found to produce excellent anesthesia with rapid Ketamine and PCP can directly act on dopaminergic receptors or

onset (Domino, 2010). In 1964, this newly-synthesized drug was block NMDA receptors to increase the release of dopamine; and

introduced into clinical human studies and produced remarkable dopamine dysfunction in brains may trigger the underlying mech-

anesthesia with minimal side effects. Soon thereafter, physicians anisms of schizophrenia (Javitt, 2010). Ketamine hydrochloride is

extended the application of ketamine to many clinical practices: water soluble and lipid permeable. It is readily absorbed via intra-

ophthalmic surgery (Harris et al., 1968) pediatric surgery (Del Prete venous, intramuscular, subcutaneous, epidural, oral, rectal, and

et al., 1968), neurosurgical procedures (Corssen et al., 1969), pedi- transnasal routes of administration, as well as intraperitoneal injec-

atric cardiac catheterization and other procedures (Ginsberg and tion in laboratory animals (Aroni et al., 2009; Flecknell, 1998). Brain

Gerber, 1969; Szappanyos et al., 1969; Wilson et al., 1969). A wider uptake and redistribution occur rapidly due to its low binding to

usage of ketamine in humans occurred during the Vietnam War plasma proteins. Thus, uptake and distribution of ketamine to chil-

with documented safety in resource-poor settings (Mercer, 2009). dren’s brains occurs rapidly in pediatric settings or to fetal brains

Ketamine has been widely accepted in clinical settings because of via the placental barrier in obstetric settings. Ketamine is metabo-

its profound analgesic, sedative, dissociative and amnestic effects, lized by N-demethylation and oxidation in the hepatic cytochrome

while maintaining protective airway reﬂexes, spontaneous respi- P450 system (by CYP2B6 and CYP3A4), and its primary metabo-

rations, and cardiopulmonary stability. lite, norketamine, is one third to one ﬁfth as potent as the original

With the increasing popularity of ketamine use in clinics, the compound (White et al., 1982).

psychotropic effects of ketamine attracted more and more people

to consume it as a recreational drug, or use it as a date rape drug

(Graeme, 2000; Jansen, 2000). Considering the increased abuse 3. Clinical use and complications

of ketamine and criminal offences relating to ketamine, the DEA

(Drug Enforcement Administration) listed ketamine as a Sched- Ketamine is widely used for four major clinical indica-

ule III non-narcotic substance under the Controlled Substances Act tions: anesthesia, analgesia, sedation, and antidepressant effects

in 1999. Coincidentally, in the same year, ketamine was found to (Domino, 2010). Ketamine-induced anesthesia is described as a

induce neurodegeneration in the developing brain (Ikonomidou dissociative anesthesia, characterized by profound analgesia and

et al., 1999), which led to heated discussions on the neurotox- amnesia with retention of protective airway reﬂexes, sponta-

icity of ketamine use in children. Further studies have indicated neous respirations, and cardiopulmonary stability (Green et al.,

that high doses or repeated ketamine doses can induce cell death, 2011). Under ketamine anesthesia, blood pressure is well main-

especially apoptosis, in many kinds of in vivo and in vitro mod- tained even in the presence of hypovolemia. Spontaneous breathing

els from mice, rats, and monkeys (Amr, 2010; Fredriksson et al., occurs and laryngeal reﬂexes are preserved. This makes ketamine

2004; Scallet et al., 2004; Takadera et al., 2006; Wang et al., 2005, the ‘ﬁrst choice’ anesthetic for pre-hospital anesthesia/analgesia.

2006; Zou et al., 2009a, 2009b). Also, ketamine was found to dis- Also, ketamine can be used for premedication, sedation, induc-

turb normal neurogenesis of neural stem progenitor cells (NSPCs) tion and maintenance of general anesthesia. In pediatric practices

in the developing brain (Dong et al., 2012). These ﬁndings forced combinations of ketamine with other anesthetics like propofol or

scientists and physicians to reconsider the safety and toxic effects midazolam, are utilized in pediatric plastic surgery (Zook et al.,

of ketamine in pediatric settings. Developmental neurotoxicity is 1971), oral surgery (Birkhan et al., 1971), neurosurgery (Chadduck

being explored and clariﬁed as a new complication of ketamine and Manheim, 1973), cardiac anesthesia (Koruk et al., 2010; Radnay

following its clinical use in Pediatrics. et al., 1976), ophthalmic surgery (Raju, 1980), gastrointestinal

procedures (Shemesh et al., 1982), and for diagnostic and inter-

ventional cardiac procedures (Singh et al., 2000).

2. Pharmacology Subanesthetic doses of ketamine can produce analgesic effects

as an ‘anti-hyperalgesic’, ‘anti-allodynic’ or ‘tolerance-protective’

Major pharmacological effects of ketamine are related to the agent (Visser and Schug, 2006). Ketamine is also suitable for acute

antagonism of NMDA receptors, a tetrameric protein complex that and chronic pain management (Amr, 2010; Blonk et al., 2010;

forms a ligand-gated calcium ion channel (Duchen et al., 1985; Noppers et al., 2010; Visser and Schug, 2006). Ketamine can induce

Harrison and Simmonds, 1985; Honey et al., 1985; Martin and excellent analgesic effects in patients with chronic cancer pain and

Lodge, 1985; Snell and Johnson, 1985; Thomson and Lodge, 1985; chronic neuropathic pain (Bell, 2009; Ben-Ari et al., 2007; Elsewaisy

Thomson et al., 1985). Ketamine non-competitively binds to the et al., 2010; Holtman et al., 2008; Kalina et al., 2008). Studies

phencyclidine site inside the NMDA receptor and blocks the inﬂux on chronic phencyclidine and later ketamine abusers, found that

of calcium (Bolger et al., 1986; Ffrench-Mullen and Rogawski, 1992; ketamine had antidepressant effects in depressed patients (Berman

O‘Shaughnessy and Lodge, 1988). Ketamine-produced blockade of et al., 2000; Hashimoto, 2010; Kudoh et al., 2002; Valentine et al.,

NMDA receptors depends on the opening state of the calcium ion 2011). The study of the basic mechanisms of ketamine’s antidepres-

channel in the NMDA receptor. Varying composition of NMDA sant effects may provide new lead targets to develop better agents

receptor subunits determines temporal and regional speciﬁcity and to treat psychiatric patients with major depressive disorder and

unique functional properties (Monyer et al., 1992; Paoletti and other forms of depression. In children, ketamine produces potent

Neyton, 2007). analgesia (Da Conceic¸ ão et al., 2006; Dal et al., 2007). Although

Ketamine also acts on other receptors. S(+)-ketamine can reduce ketamine was under reevaluation because of its neurotoxicity in

opioid consumption after surgery (Lahtinen et al., 2004), and the developing brain, in pediatric clinical settings, it is being used

reverse opioid tolerance in pain management (Mercadante et al., increasingly to supplement opioids for pain after major surgery

2003) indicating that it may interact with opioid receptors to (Anderson and Palmer, 2006). In the emergency department (ED),

some extent. Recent publications also indicate ketamine may stim- intensive care unit (ICU), and during invasive examination proce-

ulate dopaminergic receptors (D2) in vitro (Seeman and Guan, dures, when conscious sedation is necessary for pediatric patients,

2008; Seeman et al., 2005) with even higher afﬁnities than the ketamine is a popular choice. A large number of clinical studies

NMDA receptors (Kapur and Seeman, 2002; Seeman and Guan, indicate that combinations of ketamine and midazolam (McGlone,

C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60 55

2009; Sener et al., 2011), ketamine and dexmedetomidine (McVey In vitro studies with neuronal cultures also conﬁrmed that

and Tobias, 2010), or ketamine and propofol (Weatherall and ketamine induced apoptosis in developing brains. In rat forebrain

Venclovas, 2010) are very useful and safe for sedation and pain cultures, 10 and 20 ␮M ketamine exposure for 12 h induced a sub-

relief in ED or ICU patients, especially during ventilator manage- stantial increase of TUNEL positive cells relating to the upregulation

ment. of NR1-subunit of the NMDA receptor following ketamine adminis-

Long-term ketamine use results in impaired cognition, mem- tration (Takadera et al., 2006; Wang et al., 2005). The same doses of

ory and mood. Prolonged exposure to ketamine can up-regulate ketamine also alleviate apoptotic level in cultured frontal cortical

D1 receptor activity in the dorsal–lateral prefrontal cortex, neurons isolated from a monkey at PND 3 (Wang et al., 2006). Addi-

which impairs the memory and judgment of chronic recreational tionally, although low, subanesthetic concentrations of ketamine

ketamine abusers (Narendran et al., 2005). Subanesthetic doses do not affect cell survival, it can impair neuronal morphology and

of ketamine in healthy volunteers (Malhotra et al., 1996) leads to dendritic arbor development in immature GABAergic neurons. This

signiﬁcant decrease in attention and semantic memory. In pharma- indicates that even low doses of ketamine can interfere with the

cological model of acute schizophrenia, short and long-term use build-up of neural networks in the developing brain (Vutskits et al.,

of ketamine impaired semantic control and memory, mimicking 2007, 2006).

schizophrenia (Morgan et al., 2006). In a long run, the developmental complications of ketamine

Recent reports show that ketamine use in newborn animals neurotoxicity create important issues for both clinician and scien-

results in long lasting cognitive deﬁcits in rats and rhesus monkeys tists. Based on present proposed mechanisms of ketamine-induced

(Paule et al., 2011; Young et al., 2005). Ketamine is listed as an apoptosis, ketamine can upregulate NMDA receptor expression in

illicit club drug and is mainly abused among the teenagers and cultured neurons (Wang et al., 2005). Increased NMDA receptors

young adults at bars, nightclubs, and parties. Low-dose intoxi- can promote calcium inﬂux under normal amounts of gluta-

cation impairs attention, learning ability, and memory (Morgan mate, which may trigger both apoptotic and excitotoxic cell death

and Curran, 2006; Morgan et al., 2009, 2010). At higher doses, (Anand and Scalzo, 2000). Up-regulated NR1 may directly mediate

ketamine can cause dreamlike states and hallucinations and even ketamine-induced cell death via some unknown pathways and not

lead to delirium and amnesia. Ketamine is used recreationally as a via calcium inﬂux (Fig. 1). Although there is a heated controversy

club drug because it decreases social inhibitions and is thought to on the neurotoxic role of ketamine, multiple lines of evidence sug-

heighten the sexual experience (Parks and Kennedy, 2004), which gest that ketamine can affect the expression of NMDAR as well as

can increase the incidence of unintended pregnancy (Romanelli the neuronal fate during normal development.

et al., 2003; Semple et al., 2009). These pregnant mothers may have

other opportunities to abuse large doses of ketamine long term.

Ketamine can easily cross the placenta, enter the fetal circulation 5. Ketamine alters the neurogenesis of early developing

(Craven, 2007), and rapidly distribute to the embryonic/fetal brain. brains

This situation results in greater chances for ketamine to alter the

development of embryonic brains. Thus, it is necessary to deﬁne the Neurogenesis is deﬁned as the process generating new nerve

dose- and time-dependent effects of ketamine on neural stem pro- cells. Neurogenesis initiated from neural stem cells and resulting in

genitor cells for a reevaluation of the risk of ketamine as an abuse functional new neurons, is a fundamental process for both embry-

drug. onic neurodevelopment and adult brain plasticity (Shi et al., 2010).

In a wider concept, neurogenesis is a process of creating properly

functional neurons, including neural stem cell proliferation and fate

4. Ketamine induces cell death in developing brains speciﬁcation, neuronal migration, maturation, and integration into

neural networks. Neurogenesis from undifferentiated neural stem

During the brain growth spurt period of the developing brain, progenitor cells (NSPCs) determines the cellular quantity in the

neuronal apoptosis can be triggered by the blockade of NMDA developing brain and the formation of neurons, astrocytes, oligo-

receptors. Experimental evidence has conﬁrmed the fact that high dendroglia, and other neural lineages. Meanwhile, NSPCs replenish

doses of ketamine trigger cell death in the developing brain. In the undifferentiated cell pool via continued proliferation. Thus, any

1999, a classic study by Ikonomidow et al. reported that prolonged chemicals or drugs interfering in the neurogenesis of NSPCs in the

ketamine anesthesia enhanced neuronal cell death in neonatal rats developing brain can alter normal development of the brain. In

(Ikonomidou et al., 1999). Scallet et al. reported that repeated doses developmental neurotoxicological studies, NSPCs can serve as an

of 20 mg/kg ketamine increased the number of degenerating neu- ideal tool to clarify and evaluate potential risks of various toxic

rons in neonatal rats at postnatal day (PND) 7 (Scallet et al., 2004). In factors in the developing brain (Breier et al., 2010).

neonatal mice, high doses of ketamine induced severe degeneration The NMDA receptor is one type of inotropic calcium chan-

of cells in the parietal cortex, with apparent deﬁcits in habituation, nel receptor, composed of obligatory NR1 and regulatory NR2

acquisition learning, and retention memory at the age of 2 months (NR2A-D) and/or NR3 (NR3A-B) subunits (Furukawa et al., 2005).

(Fredriksson and Archer, 2004; Fredriksson et al., 2004). Rudin The expression of NMDA receptor subunits presents developmen-

et al. reported that a clinically relevant single dose of ketamine can tal stage-dependent and brain region-dependent differences in

produce long-lasting neuronal apoptosis in certain brain areas of the developing brain. The expression patterns of NMDA receptor

neonatal mice at PND7 (Rudin et al., 2005). Slikker et al. showed subunits in different brain regions can be regulated as develop-

that monkeys at the earlier developmental stage are more sen- ment proceeds. Compared to the wide distribution of NR1-subunit

sitive to ketamine-induced cell death. Small doses of ketamine expression throughout the CNS at all ages, the expression proﬁles

with short term exposure did not lead to cell death in the new- of the NR2subunits in the brain are developmentally and regionally

born monkey at PND5 (Slikker et al., 2007), but long term ketamine regulated (Ishii et al., 1993). Neural stem progenitor cells are con-

exposure produced extensive increases in the number of caspase- sidered to have no or little expression of NMDA receptors until they

3 positive neurons in infant monkey brains (Zou et al., 2009a). are completely differentiated. Previous studies directly detected

Furthermore, a recent study has indicated that ketamine-induced the expression of NMDA receptor subunits in NSPCs from different

neuronal cell death in the developing brain may be associated with sources. Immunocytochemical analysis showed expression of NR1,

very long-lasting deﬁcits in brain function in primates (Paule et al., NR2A, and NR2B subunits in cultured neurospheres (Joo et al., 2007;

2011). Kitayama et al., 2004; Mochizuki et al., 2007; Ramirez and Lamas,

56 C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60

Fig. 1. Developmental neurotoxic effects of ketamine on NSPCs and developing neurons in the developing brain.

During normal brain development, neural stem progenitor cells including neural stem cells (NSCs) and neural progenitor cells (NPCs), differentiate into neurons following

a normal development program. In this maturation process, the expression of NMDA receptor subunits is regulated in developmental stage and brain regions dependent

manners. Also, functions of NMDA receptors turn into being mature after a complete differentiation. However, ketamine can disturb normal expression patterns of NMDA

receptors, leading to pre-maturation of functional NMDA receptors. In this scenario, NSPCs have lower proliferative ability and differentiate into neurons at the earlier

developmental stage. More functional NMDA receptors expressed in these pre-matured neurons can make themselves susceptible to ketamine-induced cell death. As a

result, normal developmental patterns of a brain is reset to an earlier developmental stage and further brain structure and functions could be disordered, under the exposure

to ketamine.

2009). The expression of NMDA receptors containing NR1 and NR2B of the other NMDA receptor subunits does not change in the cere-

were found in human neural progenitor cells and NR2B was the bral cortex following drug treatment (Sircar et al., 1996). For NSPCs,

predominant NR2 subunit (Hu et al., 2008; Suzuki et al., 2006; our unpublished data showed that ketamine can dose-dependently

Wegner et al., 2009; Zhang et al., 2004). The expression patterns of upregulate NR1 expression in rat fetal cortical NSPCs. The upre-

NMDA receptor subunits in NSPC cultures are also time-dependent. gulated NR1 expression may increase the proportion of functional

NR2A, NR2B, and NR2D subunit transcripts are present in both non- NMDA receptors in differentiating NSPCs and enhance the suscep-

differentiated and neuronally differentiated cultures, while NR2C tibility of neural progenitor cells at the late differentiation stage to

subunits were expressed only transiently during the early period ketamine (Fig. 1).

of neural differentiation. NR1 and NR2B can be detected in rat fetal In the mammalian brain, amino acid neurotransmitters, gluta-

cortical NSPCs, but the calcium current cannot be recorded in these mate and aspartate, mediate mainly excitatory neurotransmission.

cultures (Yoneyama et al., 2008). This ﬁnding implies that NSPCs High levels of glutamate are found during neurogenesis in several

have already expressed NMDA receptors but these receptors may CNS developing areas (Benitez-Diaz et al., 2003; Miranda-Contreras

be nonfunctional (Dong et al., 2012). Other studies also support et al., 1999, 1998, 2000). Therefore, the antagonism of NMDA

that functional NMDA receptors are absent in NSPCs until a cer- receptors is possibly involved in disturbing the normal process of

tain stage of neuronal commitment or the appearance of synaptic neurogenesis, proliferation and differentiation of NSPCs during the

communication despite of the expression of their subunits (Jelitai CNS development.

et al., 2002; Muth-Kohne et al., 2010; Varju et al., 2001). We found

that ketamine does not induce cell death in the in vitro cultured 5.1. Proliferation

rat fetal cortical NSPCs (Dong et al., 2012). This ﬁnding could be

explained by no expression of functional NMDA receptors in NSPCs. Proliferation of neural stem progenitor cells is changed under

Some studies showed even high levels of glutamate, up to 1 mM the exposure to glutamate or glutamate receptor antagonists.

fail to induce toxic effects in neural precursor cultures until late Proliferation and neuronal differentiation of hippocampal neu-

stages of neuronal differentiation (Brazel et al., 2005; Buzanska ral progenitor cells were increased by the activation of NDMA

et al., 2009; Hsieh et al., 2003). Therefore, compared with primary receptors (Joo et al., 2007). Proliferative state of rat hippocampal

neuronal cells, NSPCs appear to have a high resistance to neurotox- progenitor cells is associated with low level NMDA-induced cur-

icity induced by glutamate or NMDAR antagonists like ketamine rent (Sah et al., 1997). Sustained exposure to NMDAR antagonist

(Fig. 1). decreases the diameter and number of neurospheres formed by

The developmental patterns of NMDA receptor subunit expres- hippocampal neural progenitor cells (Mochizuki et al., 2007). The

sion can be regulated by NMDA receptor antagonists like PCP, proliferation of striatal neuronal progenitors also is enhanced by

MK-801, and ketamine. Acute exposure to PCP at PND7 increases glutamate exposure in vivo and in vitro by an NMDA receptor-

membrane levels of both NR1 and NR2B proteins in the frontal mediated mechanism (Luk et al., 2003; Luk and Sadikot, 2001;

cortex; but decreases NR1 and NR2B levels in the endoplasmic reti- Sadikot et al., 1998). In the models of human and rat NSPCs from the

culum fraction (Anastasio and Johnson, 2008). Remarkable increase fetal cortex, the activation of glutamate receptors also stimulates

in NR1mRNA signals appear in the frontal cortex under the expo- the increase of cell division (Luk and Sadikot, 2004; Suzuki et al.,

sure of ketamine in situ hybridization assay (Zou et al., 2009b). 2006). Another in vivo study reported that the glutamate release

NMDA receptor subunits mRNA in the developing brain are rapidly following perinatal hypoxia/ischemia may act to acutely promote

altered under the exposure to MK-801. The increase of NR2A mRNA the proliferation of multipotent precursors in the subventricular

is greater than NR1, NR2B or NR2D (Wilson et al., 1998). Chronic zone (Brazel et al., 2005). NMDA receptor activation also induces

PCP administration in postnatal rats produces signiﬁcant reduction postnatal Müller glia-derived retinal cell progenitor proliferation

in NR2B subunits in the cerebral cortex, whereas the expression both in culture and in vivo (Ramirez and Lamas, 2009).

C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60 57

In contrast, a couple of studies using hippocampal progeni- the proliferation as well as promote differentiation in progenitor

tor cells show an opposite effect that NMDA exposure reduces cells.

the proliferation ability and inhibits the formation of neuro- NMDA receptors also appear to be involved in determining the

spheres (Yoneyama et al., 2008). The inhibition of the proliferation differentiation direction in NSPCs. Astrocytic nestin expression in

in hippocampal NPCs (neural progenitor cells) is mediated by less differentiated CNS cells is mediated by NMDA receptors. MK-

NMDA receptors and is regulated by the transient expression of 801 treatment can inhibit NMDA receptor dependent astrocytic

NMDA receptors (Kitayama et al., 2004, 2003). Another NMDA nestin expression, suggesting the antagonism of NMDA recep-

receptor antagonist, memantine can increase the proliferation of tors may inhibit the commitment of NSPCs to glial differentiation

hippocampal progenitor cells by inducing up-regulation of Pigment (Holmin et al., 2001). In NMDA-treated retinas, the differentia-

Epithelium Derived Factor (PEDF) (Namba et al., 2010). Addition- tion of NPCs preferred the glial lineage through gp130 signaling

ally, in the mouse hippocampal slice cultures, NMDA triggers (Mawatari et al., 2005). A recent study also reported that functional

delayed neuroblast proliferation in the dentate gyrus (Bunk et al., NMDA receptor subunits are expressed in glia (Schipke et al., 2001).

2010). Glutamate may stimulate the phosphorylation of glial ﬁbrillary

Obviously, the effects of NMDAR activities on the proliferation acidic protein (GFAP) via NMDA receptors in cortical microslices

of NSPCs are different in the NSPCs isolated from different brain and in mixed neuronal/glial cell cultures prepared from the cerebel-

regions. This difference may be associated with the temporal and lum (Kommers et al., 2002). These data present us some clues for the

brain regional speciﬁc characteristics of the expression patterns of involvement of NMDA receptors in determining the differentiation

NMDAR subunits. NSPCs in different brain regions at certain devel- direction of NSPCs.

opment stage have a different composition of NMDAR subunits, Calcium inﬂux may play a role in the neuronal differentiation

resulting in different responses of NMDAR activity on proliferation. of NPSCs. On examining the expression of NMDAR in NSPCs, it is

Additionally, NMDAR activity induced proliferation changes may evident that there are few, if any, functional NMDA receptors on

not be directly mediated by functional NMDAR, but by growth fac- NSPCs, which explains the resistance of NSPCs to ketamine-induced

tors generated by NSPCs under the exposure of NMDAR agonists neurotoxic effects. Previous studies show that ketamine can induce

or antagonists (Namba et al., 2010). The expression of functional the expression of NR1 in mature neurons (Wang et al., 2005) and in

channels and receptors in primary cultures of progenitor cells is NSPCs(Dong et al., 2012). Ketamine exposure induces the expres-

regulated by growth factors such as BDNF, and NT-3 from NSPCs sion of NMDAR subunits to build up more functional NMDAR as

(Sah et al., 1997). Proliferation changes in the developing brain, the differentiation proceeds. These newly-induced NMDA recep-

resulting from ketamine exposure may be related to ketamine- tors can trigger calcium inﬂux to promote neuronal differentiation

altered growth factors levels secreted from NSPCs. (Fig. 1). This may indicate a potential mechanism for ketamine-

enhanced neuronal differentiation in NSPCs.

5.2. Differentiation

6. Conclusions

Glutamate is currently recognized as a regulator in the neu-

ral differentiation of NSPCs (Bading et al., 1995). Its application

Ketamine is widely used as an anesthetic, analgesic, and seda-

to postnatal rat whole-brain dissociated cell cultures promotes

tive in obstetric and pediatric settings and also as an illicit club

neuronal growth and differentiation (Aruffo et al., 1987). NMDAR

drug consumed by pregnant drug abusers. Also, extrapolating from

activation promotes neurite outgrowth from cerebellar granule

adult studies, the off-label use of ketamine has been explored as

cells (Pearce et al., 1987) and dendritic outgrowth and branch-

an antidepressant in the treatment of pediatric bipolar disorders

ing of hippocampal cells (Brewer and Cotman, 1989; Huerta et al.,

(Papolos et al., 2012). Despite this widespread use, many lines of

2000; Mattson and Kater, 1988). Additionally, activation of NMDAR

evidence indicate that ketamine can induce neuronal cell death of

transiently expressed in undifferentiated NPCs in fetal rat neo-

and disturb the normal neurogenesis of NSPCs in the developing

cortex promotes neuronal differentiation (Yoneyama et al., 2008).

brain, via effects on both proliferation and differentiation. Recent

Excitatory stimuli act directly on adult hippocampal NPCs, which

studies have already indicated that ketamine can result in long-

can increase neuronal production. The excitation mediated via l-

2+ lasting cognitive deﬁcits in a primate model (Paule et al., 2011).

type Ca channels and NMDAR on the proliferating precursors can

Developmental neurotoxic effects of ketamine should be investi-

inhibit expression of the glial fate genes Hes1 and Id2 and increase

gated as a new clinical complication resulting from ketamine use

the expression of NeuroD, a positive regulator of neuronal differen-

in large doses and/or for prolonged periods of time, in obstetric and

tiation (Deisseroth et al., 2004). Enhanced neuronal differentiation

2+ pediatric clinical practices and in the setting of drug abuse.

in NPCs is regulated by complex interactions between Ca inﬂux

and excitation-releasable cytokines, even at mild levels of excita-

tion (Joo et al., 2007). 7. Future directions

The precise cellular role of NMDAR in the neuronal differentia-

tion of NSPCs remains unclear due to quite a few opposing opinions. Current ﬁndings that ketamine induces neuronal cell death and

In hippocampal slice cultures, the exposure to IGF-I and EGF and alters neurogenesis in the developing brain are based on animal

NMDA receptor antagonists MK-801 or APV increases granule cell studies, mostly in rodents and primates. Clearly, future ketamine

neurogenesis from preexisting neural precursors (Poulsen et al., studies must clarify whether ketamine can induce the same toxic

2005). The increase of Ca inﬂux mediated by NMDA receptors effects in the developing human brain. Well-designed studies are

is accompanied with decreased neuronal marker-microtubules- needed to systematically evaluate the potential developmental

associated protein-2 (MAP2) expression in hippocampal neurons neurotoxic proﬁle of current ketamine use protocols in pediatric

cultured under static magnetism without cell death (Nakamichi and obstetric practice.

et al., 2009). Moreover, in human neuroblastoma, cells having stem Furthermore, it is critical to further elucidate the mechanisms by

cell-like qualities, a signaling cascade, including Ca inﬂux and which ketamine-induced NMDA receptor antagonism leads to cell

NMDA receptor activity, is identiﬁed as playing a role in the regu- death in mature neurons and altered neurogenesis in neural stem

lation of neurogenesis. This pathway functions to maintain BE(2)C progenitor cells. Once the speciﬁc NMDA receptor subunits or cell

cells in an undifferentiated, proliferative state. Therefore, it is still signaling pathways are identiﬁed that result in those toxic effects,

necessary to clarify whether NMDA receptor antagonist can inhibit novel compounds or derivatives of ketamine that are more selective

58 C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60

for NMDA receptor subunits or activate other cell signaling path- Deisseroth, K., Singla, S., Toda, H., Monje, M., Palmer, T.D., Malenka, R.C., 2004.

Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron

ways can be developed. As for other clinically used NMDA receptor

42, 535–552.

antagonists like dextromethorphan, amantadine, and memantine,

Del Prete, S., Margaria, E., Bosio, U., 1968. CI-581 in pediatric surgery. Minerva

the potential developmental neurotoxic proﬁles in their clinical use Anestesiologica 34, 1376–1378.

Domino, E.F., 2010. Taming the ketamine tiger. 1965. Anesthesiology 113, 678–684.

also need to be evaluated further. A wider collaboration among lab-

Dong, C., Rovnaghi, C.R., Anand, K.J.S., 2012. Ketamine alters the neurogenesis of rat

oratory investigators, clinician-scientists, and pediatric physicians

cortical neural stem progenitor cells. Critical Care Medicine 40, 2407–2416.

will explicate the developmental neurotoxic effects of ketamine Duchen, M.R., Burton, N.R., Biscoe, T.J., 1985. An intracellular study of the interac-

tions of N-methyl-dl-aspartate with ketamine in the mouse hippocampal slice.

and promote safe and effective clinical use of ketamine in the future.

Brain Research 342, 149–153.

Elsewaisy, O., Slon, B., Monagle, J., 2010. Analgesic effect of subanesthetic intra-

venous ketamine in refractory neuropathic pain: a case report. Pain Medication

Conﬂict of interest statement

11, 946–950.

Ffrench-Mullen, J.M., Rogawski, M.A., 1992. Phencyclidine block of calcium cur-

rent in isolated guinea-pig hippocampal neurones. Journal of Physiology 456,

The authors declare that there are no conﬂicts of interest.

85–105.

Flecknell, P., 1998. Laboratory Animal Anaesthesia. Academic Press, London.

Fredriksson, A., Archer, T., 2004. Neurobehavioural deﬁcits associated with apop-

References totic neurodegeneration and vulnerability for ADHD. Neurotoxicity Research 6,

435–456.

Amr, Y.M., 2010. Multi-day low dose ketamine infusion as adjuvant to oral Fredriksson, A., Archer, T., Alm, H., Gordh, T., Eriksson, P., 2004. Neurofunctional

gabapentin in spinal cord injury related chronic pain: a prospective, randomized, deﬁcits and potentiated apoptosis by neonatal NMDA antagonist administration.

double blind trial. Pain Physician 13, 245–249. Behavioural Brain Research 153, 367–376.

Anand, K.J.S., Scalzo, F.M., 2000. Can adverse neonatal experiences alter brain devel- Furukawa, H., Singh, S.K., Mancusso, R., Gouaux, E., 2005. Subunit arrangement and

opment and subsequent behavior? Biology of the Neonate 77, 69–82. function in NMDA receptors. Nature 438, 185–192.

Anastasio, N.C., Johnson, K.M., 2008. Differential regulation of the NMDA receptor Gilmour, G., Dix, S., Fellini, L., Gastambide, F., Plath, N., Steckler, T., Talpos, J., Trick-

by acute and sub-chronic phencyclidine administration in the developing rat. lebank, M., 2012. NMDA receptors, cognition and schizophrenia – testing the

Journal of Neurochemistry 104, 1210–1218. validity of the NMDA receptor hypofunction hypothesis. Neuropharmacology

Anderson, B.J., Palmer, G.M., 2006. Recent developments in the pharmacologi- 62, 1401–1412.

cal management of pain in children. Current Opinion in Anaesthesiology 19, Ginsberg, H., Gerber, J.A., 1969. Ketamine hydrochloride: a clinical investigation in

285–292. 60 children. South African Medical Journal 43, 627–628.

Aroni, F., Iacovidou, N., Dontas, I., Pourzitaki, C., Xanthos, T., 2009. Pharmacological Graeme, K.A., 2000. New drugs of abuse. Emergency Medicine Clinics of North

aspects and potential new clinical applications of ketamine: reevaluation of an America 18, 625–636.

old drug. Journal of Clinical Pharmacology 49, 957–964. Green, S.M., Roback, M.G., Kennedy, R.M., Krauss, B., 2011. Clinical practice guideline

Aruffo, C., Ferszt, R., Hildebrandt, A.G., Cervos-Navarro, J., 1987. Low doses of l- for emergency department ketamine dissociative sedation: 2011 update. Annals

monosodium glutamate promote neuronal growth and differentiation in vitro. of Emergency Medicine 57, 449–461.

Developmental Neuroscience 9, 228–239. Harris, J.E., Letson, R.D., Buckley, J.J., 1968. The use of CI-581, a new parenteral anes-

Bading, H., Segal, M.M., Sucher, N.J., Dudek, H., Lipton, S.A., Greenberg, M.E., 1995. N- thetic, in ophthalmic practice. Transactions of the American Ophthalmological

methyl-d-aspartate receptors are critical for mediating the effects of glutamate Society 66, 206–213.

on intracellular calcium concentration and immediate early gene expression in Harrison, N.L., Simmonds, M.A., 1985. Quantitative studies on some antagonists of

cultured hippocampal neurons. Neuroscience 64, 653–664. N-methyl- -aspartate in slices of rat cerebral cortex. British Journal of Pharma-

Bell, R.F., 2009. Ketamine for chronic non-cancer pain. Pain 141, 210–214. cology 84, 381–391.

Ben-Ari, A., Lewis, M.C., Davidson, E., 2007. Chronic administration of ketamine for Hashimoto, K., 2010. The role of glutamate on the action of antidepressants. Progress

analgesia. Journal of Pain Palliat Care Pharmacotherapy 21, 7–14. in Neuro-Psychopharmacology and Biological Psychiatry 35, 1558–1568.

Benitez-Diaz, P., Miranda-Contreras, L., Mendoza-Briceno, R.V., Pena-Contreras, Z., Holmin, S., von Gertten, C., Sandberg-Nordqvist, A.C., Lendahl, U., Mathiesen, T.,

Palacios-Pru, E., 2003. Prenatal and postnatal contents of amino acid neurotrans- 2001. Induction of astrocytic nestin expression by depolarization in rats. Neu-

mitters in mouse parietal cortex. Developmental Neuroscience 25, 366–374. roscience Letters 314, 151–155.

Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., Holtman Jr., J.R., Crooks, P.A., Johnson-Hardy, J.K., Hojomat, M., Kleven, M., Wala,

Krystal, J.H., 2000. Antidepressant effects of ketamine in depressed patients. E.P., 2008. Effects of norketamine enantiomers in rodent models of persistent

Biological Psychiatry 47, 351–354. pain. Pharmacology Biochemistry and Behavior 90, 676–685.

Birkhan, J., Shamash, R., Gutman, D., 1971. Ketamine-dissociative anesthesia in Honey, C.R., Miljkovic, Z., MacDonald, J.F., 1985. Ketamine and phencyclidine cause

pediatric oral surgery. Journal of Oral Surgery 29, 853–857. a voltage-dependent block of responses to -aspartic acid. Neuroscience Letters

Blonk, M.I., Koder, B.G., van den Bemt, P.M., Huygen, F.J., 2010. Use of oral ketamine 61, 135–139.

in chronic pain management: a review. European Journal of Pain 14, 466–472. Hsieh, W.Y., Hsieh, Y.L., Liu, D.D., Yang, S.N., Wu, J.N., 2003. Neural progenitor

Bolger, G.T., Rafferty, M.F., Skolnick, P., 1986. Enhancement of brain calcium cells resist excitatory amino acid-induced neurotoxicity. Journal of Neuroscience

antagonist binding by phencyclidine and related compounds. Pharmacology Research 71, 272–278.

Biochemistry and Behavior 24, 417–423. Hu, M., Sun, Y.J., Zhou, Q.G., Chen, L., Hu, Y., Luo, C.X., Wu, J.Y., Xu, J.S., Li, L.X., Zhu,

Brazel, C.Y., Nunez, J.L., Yang, Z., Levison, S.W., 2005. Glutamate enhances survival D.Y., 2008. Negative regulation of neurogenesis and spatial memory by NR2B-

and proliferation of neural progenitors derived from the subventricular zone. containing NMDA receptors. Journal of Neurochemistry 106, 1900–1913.

Neuroscience 131, 55–65. Huerta, P.T., Sun, L.D., Wilson, M.A., Tonegawa, S., 2000. Formation of temporal

Breier, J.M., Gassmann, K., Kayser, R., Stegeman, H., De Groot, D., Fritsche, E., Shafer, memory requires NMDA receptors within CA1 pyramidal neurons. Neuron 25,

T.J., 2010. Neural progenitor cells as models for high-throughput screens of 473–480.

developmental neurotoxicity: state of the science. Neurotoxicology and Tera- Ikonomidou, C., Bosch, F., Miksa, M., Bittigau, P., Vockler, J., Dikranian, K., Tenkova,

tology 32, 4–15. T.I., Stefovska, V., Turski, L., Olney, J.W., 1999. Blockade of NMDA receptors and

Brewer, G.J., Cotman, C.W., 1989. NMDA receptor regulation of neuronal morphol- apoptotic neurodegeneration in the developing brain. Science 283, 70–74.

ogy in cultured hippocampal neurons. Neuroscience Letters 99, 268–273. Ishii, T., Moriyoshi, K., Sugihara, H., Sakurada, K., Kadotani, H., Yokoi, M., Akazawa, C.,

Bunk, E.C., Konig, H.G., Bonner, H.P., Kirby, B.P., Prehn, J.H., 2010. NMDA-induced Shigemoto, R., Mizuno, N., Masu, M., et al., 1993. Molecular characterization of

injury of mouse organotypic hippocampal slice cultures triggers delayed neu- the family of the N-methyl- -aspartate receptor subunits. Journal of Biological

roblast proliferation in the dentate gyrus: an in vitro model for the study of Chemistry 268, 2836–2843.

neural precursor cell proliferation. Brain Research 1359, 22–32. Jansen, K.L., 2000. A review of the nonmedical use of ketamine: use, users and

Buzanska, L., Sypecka, J., Nerini-Molteni, S., Compagnoni, A., Hogberg, H.T., del consequences. Journal of Psychoactive Drugs 32, 419–433.

Torchio, R., Domanska-Janik, K., Zimmer, J., Coecke, S., 2009. A human stem cell- Javitt, D.C., 2010. Glutamatergic theories of schizophrenia. Israel Journal of Psychi-

based model for identifying adverse effects of organic and inorganic chemicals atry and Related Sciences 47, 4–16.

on the developing nervous system. Stem Cells 27, 2591–2601. Jelitai, M., Schlett, K., Varju, P., Eisel, U., Madarasz, E., 2002. Regulated appear-

Chadduck, W.M., Manheim, A., 1973. Ketamine anesthesia for pediatric neurosur- ance of NMDA receptor subunits and channel functions during in vitro neuronal

gical procedures. Virginia Medical Monthly (1918) 100, 333–335. differentiation. Journal of Neurobiology 51, 54–65.

Corssen, G., Groves, E.H., Gomez, S., Allen, R.J., 1969. Ketamine: its place for neuro- Joo, J.Y., Kim, B.W., Lee, J.S., Park, J.Y., Kim, S., Yun, Y.J., Lee, S.H., Rhim, H., Son,

surgical diagnostic procedures. Anesthesia and Analgesia 48, 181–188. H., 2007. Activation of NMDA receptors increases proliferation and differ-

Craven, R., 2007. Ketamine. Anaesthesia 62 (Suppl. 1), 48–53. entiation of hippocampal neural progenitor cells. Journal of Cell Science 120,

Da Conceic¸ ão, M.J., Da Conceic¸ ão, D.B., Carneiro Leao, C., 2006. Effect of an intra- 1358–1370.

venous single dose of ketamine on postoperative pain in tonsillectomy patients. Kalina, C.M., Haag, A.B., Brown, N.D., 2008. How can case managers incorporate

Pediatric Anesthesia 16, 962–967. health promotion into their practices? AAOHN Journal 56, 95–97.

Dal, D., Celebi, N., Elvan, E.G., Celiker, V., Aypar, U., 2007. The efﬁcacy of intravenous Kapur, S., Seeman, P., 2002. NMDA receptor antagonists ketamine and PCP

or peritonsillar inﬁltration of ketamine for postoperative pain relief in children have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-

following adenotonsillectomy. Paediatric Anaesthesia 17, 263–269. implications for models of schizophrenia. Molecular Psychiatry 7, 837–844.

C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60 59

Kitayama, T., Yoneyama, M., Tamaki, K., Yoneda, Y., 2004. Regulation of neuronal dif- radial glia-like neural stem cells. Molecular and Cellular Neurosciences 43,

ferentiation by N-methyl-d-aspartate receptors expressed in neural progenitor 209–221.

cells isolated from adult mouse hippocampus. Journal of Neuroscience Research Nakamichi, N., Ishioka, Y., Hirai, T., Ozawa, S., Tachibana, M., Nakamura, N., Takarada,

76, 599–612. T., Yoneda, Y., 2009. Possible promotion of neuronal differentiation in fetal

Kitayama, T., Yoneyama, M., Yoneda, Y., 2003. Possible regulation by N-methyl-d- rat brain neural progenitor cells after sustained exposure to static magnetism.

aspartate receptors of proliferative progenitor cells expressed in adult mouse Journal of Neuroscience Research 87, 2406–2417.

hippocampal dentate gyrus. Journal of Neurochemistry 84, 767–780. Namba, T., Yabe, T., Gonda, Y., Ichikawa, N., Sanagi, T., Arikawa-Hirasawa, E.,

Kommers, T., Rodnight, R., Boeck, C., Vendite, D., Oliveira, D., Horn, J., Oppelt, D., Mochizuki, H., Kohsaka, S., Uchino, S., 2010. Pigment epithelium-derived factor

Wofchuk, S., 2002. Phosphorylation of glial ﬁbrillary acidic protein is stimu- up-regulation induced by memantine, an N-methyl-d-aspartate receptor antag-

lated by glutamate via NMDA receptors in cortical microslices and in mixed onist, is involved in increased proliferation of hippocampal progenitor cells.

neuronal/glial cell cultures prepared from the cerebellum. Brain Research. Neuroscience 167, 372–383.

Developmental Brain Research 137, 139–148. Narendran, R., Frankle, W.G., Keefe, R., Gil, R., Martinez, D., Slifstein, M., Kegeles,

Koruk, S., Mizrak, A., Kaya Ugur, B., Ilhan, O., Baspinar, O., Oner, U., 2010. Propo- L.S., Talbot, P.S., Huang, Y., Hwang, D.R., Khenissi, L., Cooper, T.B., Laruelle, M.,

fol/dexmedetomidine and propofol/ketamine combinations for anesthesia in Abi-Dargham, A., 2005. Altered prefrontal dopaminergic function in chronic

pediatric patients undergoing transcatheter atrial septal defect closure: a recreational ketamine users. American Journal of Psychiatry 162, 2352–2359.

prospective randomized study. Clinical Therapeutics 32, 701–709. Noppers, I., Niesters, M., Aarts, L., Smith, T., Sarton, E., Dahan, A., 2010. Ketamine for

Kudoh, A., Takahira, Y., Katagai, H., Takazawa, T., 2002. Small-dose ketamine the treatment of chronic non-cancer pain. Expert Opinion on Pharmacotherapy

improves the postoperative state of depressed patients. Anesthesia and Anal- 11, 2417–2429.

gesia 95, 114–118, table of contents. O‘Shaughnessy, C.T., Lodge, D., 1988. N-methyl-d-aspartate receptor-mediated

Lahtinen, P., Kokki, H., Hakala, T., Hynynen, M., 2004. S(+)-ketamine as an anal- increase in intracellular calcium is reduced by ketamine and phencyclidine.

gesic adjunct reduces opioid consumption after cardiac surgery. Anesthesia and European Journal of Pharmacology 153, 201–209.

Analgesia 99, 1295–1301, table of contents. Paoletti, P., Neyton, J., 2007. NMDA receptor subunits: function and pharmacology.

Luk, K.C., Kennedy, T.E., Sadikot, A.F., 2003. Glutamate promotes proliferation of stri- Current Opinion in Pharmacology 7, 39–47.

atal neuronal progenitors by an NMDA receptor-mediated mechanism. Journal Papolos, D.F., Teicher, M.H., Faedda, G.L., Murphy, P., Mattis, S., 2012. Clinical

of Neuroscience 23, 2239–2250. experience using intranasal ketamine in the treatment of pediatric bipolar dis-

Luk, K.C., Sadikot, A.F., 2001. GABA promotes survival but not proliferation of order/fear of harm phenotype. Journal of Affective Disorders 147, 431–436.

parvalbumin-immunoreactive interneurons in rodent neostriatum: an in vivo Parks, K.A., Kennedy, C.L., 2004. Club drugs: reasons for and consequences of use.

study with stereology. Neuroscience 104, 93–103. Journal of Psychoactive Drugs 36, 295–302.

Luk, K.C., Sadikot, A.F., 2004. Glutamate and regulation of proliferation in Paule, M.G., Li, M., Allen, R.R., Liu, F., Zou, X., Hotchkiss, C., Hanig, J.P., Patterson, T.A.,

the developing mammalian telencephalon. Developmental Neuroscience 26, Slikker Jr., W., Wang, C., 2011. Ketamine anesthesia during the ﬁrst week of life

218–228. can cause long-lasting cognitive deﬁcits in rhesus monkeys. Neurotoxicology

Malhotra, A.K., Pinals, D.A., Weingartner, H., Sirocco, K., Missar, C.D., Pickar, D., Breier, and Teratology 33, 220–230.

A., 1996. NMDA receptor function and human cognition: the effects of ketamine Pearce, I.A., Cambray-Deakin, M.A., Burgoyne, R.D., 1987. Glutamate acting on NMDA

in healthy volunteers. Neuropsychopharmacology 14, 301–307. receptors stimulates neurite outgrowth from cerebellar granule cells. FEBS Let-

Martin, D., Lodge, D., 1985. Ketamine acts as a non-competitive N-methyl-d- ters 223, 143–147.

aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 24, Poulsen, F.R., Blaabjerg, M., Montero, M., Zimmer, J., 2005. Glutamate receptor

999–1003. antagonists and growth factors modulate dentate granule cell neurogenesis in

Mattson, M.P., Kater, S.B., 1988. Isolated hippocampal neurons in cryopreserved organotypic, rat hippocampal slice cultures. Brain Research 1051, 35–49.

long-term cultures: development of neuroarchitecture and sensitivity to NMDA. Radnay, P.A., Hollinger, I., Santi, A., Nagashima, H., 1976. Ketamine for pediatric

International Journal of Developmental Neuroscience 6, 439–452. cardiac anesthesia. Anaesthesist 25, 259–265.

Mawatari, Y., Fukushima, M., Inoue, T., Setoguchi, T., Taga, T., Tanihara, H., 2005. Pref- Raju, V.K., 1980. Ketamine anesthesia in pediatric ophthalmic surgery. Journal of

erential differentiation of neural progenitor cells into the glial lineage through Pediatric Ophthalmology and Strabismus 17, 292–296.

gp130 signaling in N-methyl-d-aspartate-treated retinas. Brain Research 1055, Ramirez, M., Lamas, M., 2009. NMDA receptor mediates proliferation and CREB

7–14. phosphorylation in postnatal Muller glia-derived retinal progenitors. Molecular

McGlone, R., 2009. Emergency sedation in children. Utility of low dose ketamine. Vision 15, 713–721.

BMJ 339, b5575. Romanelli, F., Smith, K.M., Pomeroy, C., 2003. Use of club drugs by HIV-seropositive

McVey, J.D., Tobias, J.D., 2010. Dexmedetomidine and ketamine for sedation during and HIV-seronegative gay and bisexual men. Topics in HIV Medications 11,

spinal anesthesia in children. Journal of Clinical Anesthesia 22, 538–545. 25–32.

Mercadante, S., Villari, P., Ferrera, P., 2003. Burst ketamine to reverse opi- Rudin, M., Ben-Abraham, R., Gazit, V., Tendler, Y., Tashlykov, V., Katz, Y., 2005.

oid tolerance in cancer pain. Journal of Pain and Symptom Management 25, Single-dose ketamine administration induces apoptosis in neonatal mouse

302–305. brain. Journal of Basic and Clinical Physiology and Pharmacology 16, 231–243.

Mercer, S.J., 2009. ‘The Drug of War’–a historical review of the use of Ketamine in Sadikot, A.F., Burhan, A.M., Belanger, M.C., Sasseville, R., 1998. NMDA recep-

military conﬂicts. Journal of the Royal Naval Medical Service 95, 145–150. tor antagonists inﬂuence early development of GABAergic interneurons in

Miranda-Contreras, L., Benitez-Diaz, P.R., Mendoza-Briceno, R.V., Delgado-Saez, the mammalian striatum. Brain Research. Developmental Brain Research 105,

M.C., Palacios-Pru, E.L., 1999. Levels of amino acid neurotransmitters during 35–42.

mouse cerebellar neurogenesis and in histotypic cerebellar cultures. Develop- Sah, D.W., Ray, J., Gage, F.H., 1997. Bipotent progenitor cell lines from the human

mental Neuroscience 21, 147–158. CNS. Nature Biotechnology 15, 574–580.

Miranda-Contreras, L., Mendoza-Briceno, R.V., Palacios-Pru, E.L., 1998. Levels of Scallet, A.C., Schmued, L.C., Slikker Jr., W., Grunberg, N., Faustino, P.J., Davis, H.,

monoamine and amino acid neurotransmitters in the developing male mouse Lester, D., Pine, P.S., Sistare, F., Hanig, J.P., 2004. Developmental neurotoxicity

hypothalamus and in histotypic hypothalamic cultures. International Journal of of ketamine: morphometric conﬁrmation, exposure parameters, and multiple

Developmental Neuroscience 16, 403–412. ﬂuorescent labeling of apoptotic neurons. Toxicological Sciences 81, 364–370.

Miranda-Contreras, L., Ramirez-Martens, L.M., Benitez-Diaz, P.R., Pena-Contreras, Schipke, C.G., Ohlemeyer, C., Matyash, M., Nolte, C., Kettenmann, H., Kirchhoff,

Z.C., Mendoza-Briceno, R.V., Palacios-Pru, E.L., 2000. Levels of amino acid neu- F., 2001. Astrocytes of the mouse neocortex express functional N-methyl-d-

rotransmitters during mouse olfactory bulb neurogenesis and in histotypic aspartate receptors. FASEB Journal 15, 1270–1272.

olfactory bulb cultures. International Journal of Developmental Neuroscience Seeman, P., Guan, H.C., 2008. Phencyclidine and glutamate agonist LY379268 stim-

18, 83–91. ulate dopamine D2High receptors: D2 basis for schizophrenia. Synapse 62,

Mochizuki, N., Takagi, N., Kurokawa, K., Kawai, T., Besshoh, S., Tanonaka, K., Takeo, 819–828.

S., 2007. Effect of NMDA receptor antagonist on proliferation of neurospheres Seeman, P., Guan, H.C., 2009. Glutamate agonist LY404,039 for treating schizophre-

from embryonic brain. Neuroscience Letters 417, 143–148. nia has afﬁnity for the dopamine D2(High) receptor. Synapse 63, 935–939.

Monyer, H., Sprengel, R., Schoepfer, R., Herb, A., Higuchi, M., Lomeli, H., Burnashev, Seeman, P., Guan, H.C., Hirbec, H., 2009. Dopamine D2High receptors stimulated by

N., Sakmann, B., Seeburg, P.H., 1992. Heteromeric NMDA receptors: molecular phencyclidines, lysergic acid diethylamide, salvinorin A, and modaﬁnil. Synapse

and functional distinction of subtypes. Science 256, 1217–1221. 63, 698–704.

Morgan, C.J., Curran, H.V., 2006. Acute and chronic effects of ketamine upon human Seeman, P., Ko, F., Tallerico, T., 2005. Dopamine receptor contribution to the action

memory: a review. Psychopharmacology 188, 408–424. of PCP, LSD and ketamine psychotomimetics. Molecular Psychiatry 10, 877–883.

Morgan, C.J., Muetzelfeldt, L., Curran, H.V., 2009. Ketamine use, cognition and psy- Seeman, P., Lasaga, M., 2005. Dopamine agonist action of phencyclidine. Synapse

chological wellbeing: a comparison of frequent, infrequent and ex-users with 58, 275–277.

polydrug and non-using controls. Addiction 104, 77–87. Semple, S.J., Strathdee, S.A., Zians, J., Patterson, T.L., 2009. Sexual risk behavior asso-

Morgan, C.J., Muetzelfeldt, L., Curran, H.V., 2010. Consequences of chronic ketamine ciated with co-administration of methamphetamine and other drugs in a sample

self-administration upon neurocognitive function and psychological wellbeing: of HIV-positive men who have sex with men. American Journal on Addictions

a 1-year longitudinal study. Addiction 105, 121–133. 18, 65–72.

Morgan, C.J., Rossell, S.L., Pepper, F., Smart, J., Blackburn, J., Brandner, B., Curran, Sener, S., Eken, C., Schultz, C.H., Serinken, M., Ozsarac, M., 2011. Ketamine with and

H.V., 2006. Semantic priming after ketamine acutely in healthy volunteers and without midazolam for emergency department sedation in adults: a randomized

following chronic self-administration in substance users. Biological Psychiatry controlled trial. Annals of Emergency Medicine 57, 109–114, e102.

59, 265–272. Shemesh, E., Bat, L., Yahav, J., Niv, Y., Jonas, A., Rozen, P., 1982. Ketamine anesthesia

Muth-Kohne, E., Terhag, J., Pahl, S., Werner, M., Joshi, I., Hollmann, M., 2010. Func- for pediatric gastrointestinal procedures. Israel Journal of Medical Sciences 18,

tional excitatory GABAA receptors precede ionotropic glutamate receptors in 760–762.

60 C. Dong, K.J.S. Anand / Toxicology Letters 220 (2013) 53–60

Shi, Y., Zhao, X., Hsieh, J., Wichterle, H., Impey, S., Banerjee, S., Neveu, P., Kosik, K.S., Vutskits, L., Gascon, E., Tassonyi, E., Kiss, J.Z., 2006. Effect of ketamine on den-

2010. MicroRNA regulation of neural stem cells and neurogenesis. Journal of dritic arbor development and survival of immature GABAergic neurons in vitro.

Neuroscience 30, 14931–14936. Toxicological Sciences 91, 540–549.

Singh, A., Girotra, S., Mehta, Y., Radhakrishnan, S., Shrivastava, S., 2000. Total Wang, C., Sadovova, N., Fu, X., Schmued, L., Scallet, A., Hanig, J., Slikker, W., 2005.

intravenous anesthesia with ketamine for pediatric interventional cardiac pro- The role of the N-methyl-d-aspartate receptor in ketamine-induced apoptosis

cedures. Journal of Cardiothoracic and Vascular Anesthesia 14, 36–39. in rat forebrain culture. Neuroscience 132, 967–977.

Sircar, R., Follesa, P., Ticku, M.K., 1996. Postnatal phencyclidine treatment differ- Wang, C., Sadovova, N., Hotchkiss, C., Fu, X., Scallet, A.C., Patterson, T.A., Hanig, J.,

entially regulates N-methyl-d-aspartate receptor subunit mRNA expression in Paule, M.G., Slikker Jr., W., 2006. Blockade of N-methyl-d-aspartate receptors

developing rat cerebral cortex. Brain Research. Molecular Brain Research 40, by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons

214–220. in culture. Toxicological Sciences 91, 192–201.

Slikker Jr., W., Zou, X., Hotchkiss, C.E., Divine, R.L., Sadovova, N., Twaddle, N.C., Weatherall, A., Venclovas, R., 2010. Experience with a propofol-ketamine mix-

Doerge, D.R., Scallet, A.C., Patterson, T.A., Hanig, J.P., Paule, M.G., Wang, C., 2007. ture for sedation during pediatric orthopedic surgery. Paediatric Anaesthesia

Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxico- 20, 1009–1016.

logical Sciences 98, 145–158. Wegner, F., Kraft, R., Busse, K., Schaarschmidt, G., Hartig, W., Schwarz, S.C., Schwarz,

Snell, L.D., Johnson, K.M., 1985. Antagonism of N-methyl-D-aspartate-induced J., 2009. Glutamate receptor properties of human mesencephalic neural pro-

transmitter release in the rat striatum by phencyclidine-like drugs and its genitor cells: NMDA enhances dopaminergic neurogenesis in vitro. Journal of

relationship to turning behavior. Journal of Pharmacology and Experimental Neurochemistry 111, 204–216.

Therapeutics 235, 50–57. White, P.F., Way, W.L., Trevor, A.J., 1982. Ketamine–its pharmacology and thera-

Suzuki, M., Nelson, A.D., Eickstaedt, J.B., Wallace, K., Wright, L.S., Svendsen, C.N., peutic uses. Anesthesiology 56, 119–136.

2006. Glutamate enhances proliferation and neurogenesis in human neural Wilson, M.A., Kinsman, S.L., Johnston, M.V., 1998. Expression of NMDA receptor

progenitor cell cultures derived from the fetal cortex. European Journal of Neu- subunit mRNA after MK-801 treatment in neonatal rats. Brain Research. Devel-

roscience 24, 645–653. opmental Brain Research 109, 211–220.

Szappanyos, G.G., Bopp, P., Fournet, P.C., 1969. The use and advantage of “Ketalar” Wilson, R.D., Traber, D.L., Evans, B.L., 1969. Correlation of psychologic and phys-

(CI-581) as anaesthetic agent in pediatric cardiac catheterisation and angiocar- iologic observations from children undergoing repeated ketamine anesthesia.

diography. Anaesthesist 18, 365–367. Anesthesia and Analgesia 48, 995–1001.

Takadera, T., Ishida, A., Ohyashiki, T., 2006. Ketamine-induced apoptosis in Yoneyama, M., Nakamichi, N., Fukui, M., Kitayama, T., Georgiev, D.D., Makanga,

cultured rat cortical neurons. Toxicology and Applied Pharmacology 210, J.O., Nakamura, N., Taniura, H., Yoneda, Y., 2008. Promotion of neuronal dif-

100–107. ferentiation through activation of N-methyl-d-aspartate receptors transiently

Thomson, A.M., Lodge, D., 1985. Selective blockade of an excitatory synapse in rat expressed by undifferentiated neural progenitor cells in fetal rat neocortex.

cerebral cortex by the sigma opiate cyclazocine: an intracellular, in vitro study. Journal of Neuroscience Research 86, 2392–2402.

Neuroscience Letters 54, 21–26. Young, C., Jevtovic-Todorovic, V., Qin, Y.Q., Tenkova, T., Wang, H., Labruyere, J., Olney,

Thomson, A.M., West, D.C., Lodge, D., 1985. An N-methylaspartate receptor- J.W., 2005. Potential of ketamine and midazolam, individually or in combination,

mediated synapse in rat cerebral cortex: a site of action of ketamine? Nature to induce apoptotic neurodegeneration in the infant mouse brain. British Journal

313, 479–481. of Pharmacology 146, 189–197.

Valentine, G.W., Mason, G.F., Gomez, R., Fasula, M., Watzl, J., Pittman, B., Krystal, Zhang, H., Lu, A., Zhao, H., Li, K., Song, S., Yan, J., Zhang, W., Wang, S., Li, L., 2004.

J.H., Sanacora, G., 2011. The antidepressant effect of ketamine is not associated Elevation of NMDAR after transplantation of neural stem cells. Neuroreport 15,

with changes in occipital amino acid neurotransmitter content as measured by 1739–1743.

[(1)H]-MRS. Psychiatry Research 191, 122–127. Zook, E.G., Roesch, R.P., Thompson, L.W., Bennett, J.E., 1971. Ketamine anesthesia in

Varju, P., Schlett, K., Eisel, U., Madarasz, E., 2001. Schedule of NMDA receptor subunit pediatric plastic surgery. Plastic and Reconstructive Surgery 48, 241–245.

expression and functional channel formation in the course of in vitro-induced Zou, X., Patterson, T.A., Divine, R.L., Sadovova, N., Zhang, X., Hanig, J.P., Paule, M.G.,

neurogenesis. Journal of Neurochemistry 77, 1444–1456. Slikker Jr., W., Wang, C., 2009a. Prolonged exposure to ketamine increases

Visser, E., Schug, S.A., 2006. The role of ketamine in pain management. Biomedicine neurodegeneration in the developing monkey brain. International Journal of

and Pharmacotherapy 60, 341–348. Developmental Neuroscience 27, 727–731.

Vutskits, L., Gascon, E., Potter, G., Tassonyi, E., Kiss, J.Z., 2007. Low concentrations Zou, X., Patterson, T.A., Sadovova, N., Twaddle, N.C., Doerge, D.R., Zhang, X., Fu, X.,

of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in Hanig, J.P., Paule, M.G., Slikker, W., Wang, C., 2009b. Potential neurotoxicity of

culture. Toxicology 234, 216–226. ketamine in the developing rat brain. Toxicological Sciences 108, 149–158.