Malaria, Anti Malarial Drugs and the Role of Melatonin

Home , Luzindole, Plasmodium malariae

Send Orders of Reprints at [email protected] Infectious Disorders – Drug Targets, 2012, 12, 371-379 371 Malaria, Anti Malarial Drugs and the Role of Melatonin

Venkataramanujam Srinivasan1, Mahaneem Mohamed2, Rahimah Zakaria2 and Asma Hayati Ahmad2

1Sri Sathya Sai Medical Educational and Research Foundation Medical Sciences Research Study Center, Prasanthi Nilayam, 40-Kovai Thirunagar, 641014,Tamilnadu, India; 2Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian Kelantan, Malaysia

Abstract: Malaria, one of the most deadly diseases of our time affects more than 200 million people across the globe and is responsible for about one million deaths annually. Until recently Plasmodium falciparum has been the main cause for malarial infection in human beings but now Plasmodium knowlesi from Malaysia remains as one of the most virulent parasite spreading fast not only in Malaysia but in different parts of the world. Hence there is urgent need for the global fight to control malaria. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria infected patients with anti-malarial drugs has helped to eliminate malarial infections suc- cessfully but with increased resistance displayed by malarial parasites to these drugs there is resurgence of malaria caused both by drug resistance as well as by infection caused by new malarial species like Plasmodium knowlesi. With recent advances on molecular studies on malarial parasites it is now clear that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence treatment modalities that can effectively block the action of melatonin on Plasmodium species during night time by way of using either bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating malarial infection in man. Keywords: Malaria, anti-malarial drugs, Plasmodium knowlesi, melatonin, Luzindole

INTRODUCTION ervoirs [2]. In the absence of transmission blocking vaccine (TBV), primaquine is the only available effective anti malar- Malaria, one of the most severe global infectious diseases ial drug that has gametocytocidal property [7. As screening is caused by a group of parasites from the genus Plasmodium of asexual blood stages of P. falciparum is considered as by one of the five different species namely P. falciparum, P. much more successful than molecular-target-based ap- Vivax, P. malariae, P. ovale and P. knowlesi. Among these proaches, new drug developments are based on this line of parasites, P. falciparum is the most dangerous and devastat- approach. The ongoing strategy for development of trans- ing one resulting in large number of deaths. According to mission blocking drugs (TBD) rests primarily on blood recent World of Health (WHO) report, more than 220 mil- scizonticides that act effectively against late stage of game- lion cases of malarial infections are reported every year with tocytes [7]. The goal of anti malarial drug therapy by should annual mortality rate of 781,000 showing thereby the urgent be directed to reduce the disease and death by targeting necessity of attending to this global problem with immediate blood stage parasites and in the case of P. flaciparum it re- attention [1]. Malaria is characterized by high fever, head- quires elimination of all persistent asexual blood stage forms ache, vomiting, chillness, shaking and anaemia. The control and the long-lived mature stage V, P. falciparum gameto- and management of malaria rests mainly on chemotherapy. cytes, responsible for transmission [8]. Studies conducted on The classical anti malarial drugs that are used include artem- Balb/C mice that luzindole, the antagonist to the pineal hor- isinin, pyronariidine, lumefantine, piperquine, chloroquinine, mone melatonin inhibited the number of trophozoites [9]. In mefloquine, pyrimethamine, atovaquone [2]. But with in- this review paper clinical features of malaria, malarial para- creasing resistance to these drugs there is need for the devel- site cell biology, anti malarial drugs, resistance to antimalar- opment and application of new innovative approaches and ial drugs, development of novel drugs, role of pineal hor- introduction of novel drugs with greater efficacy for the pos- mone melatonin in the growth and differentiation of malarial sible control and eradication of this disease [3]. The drugs parasites and possible use of anti melatonergic procedures that target the hepatic and sexual forms of malarial parasite and drugs for elimination of malarial parasites from the include artemisinin [4], primaquine [5], and artemisinin blood of the infected host will be discussed. combination therapies [6] etc. As Plasmodium sporozoites reach the mammalian within minutes after being released MOLECULAR BIOLOGY OF PLASMODIUM LIFE into the host’s blood by the infected female Anopheles mos- CYCLE quito, the drugs that act on the parasitic stages in the liver is The sporozoites that are injected into humans by a female suggested to eliminate the cryptic hypnozoite infection res- Anopheles mosquito are taken up into the liver and infect the hepatocytes. These parasites develop to form exo- *Address correspondence to this author at the Sri Sathya Sai Medical Edu- erythrocytic schizonts which give rise to several thousands cational and Research Foundation, Prasanthi Nilayam, 40-Kovai Thirunagar, of merozoites. With the rupture of liver cells merozoites are 641014, India; Cell: 0091 9790360432; E-mail: [email protected] released into the blood stream and they invade erythrocytes.

The intra erythrocytic parasites replicate synchronously and tonin as essential for synchronous maturation of Plasmodium some merozoites infecting the red blood cell (RBC) develop and its survival in the host [24]. into male and female gametocytes. These constitute the later stages of P. falciparum infection. The gametocytes are taken UBIQUITIN PROTEOSOME SYSTEM AND ITS IM- up into the female mosquito gut during the blood meal. The PORTANCE male gametocytes are activated (ex-flagellation) and form gametes which fuse with the female gametes to form diploid Egress, the parasite’s emergence from host erythrocytes ookinetes. These ookinetes migrate to the midgut of the in- involves a co-ordinated event of rupture of parasitophorous sect pass through the gut wall to form oocysts. Following the membrane (PVM) and the erythrocyte membrane (EM) and meiotic division sporozoites are formed which then migrate many proteases like aspartic proteases, cystein proteases, and to the salivary glands of the mosquito, ready for transmission a series of Serine Repeat Antigens (SERAs) are involved in into humans [10]. this process [25]. Proteases like PfCalp in P. falciparum are essential for optimal growth of the parasite and cell cycle Of these various stages outlined above, residence in the progression [26]. These proteases are the targets of anti ma- human erythrocyte is essential for the life cycle for all Plas- larial drugs due to their involvement in parasite development modium that infect man and it is this phase of the life cycle and invasion [27]. The most important protease system in P. that causes disease also. All the clinical symptoms of malaria falciparum is the ubiquitin-proteosome protein degradation like fever, anaemia, neurological manifestations are associ- system (UPS) which is responsible for degrading unwanted ated with blood stage of the Plasmodium life cycle [11]. or misfolded proteins and thereby playing an important role With the introduction of new genetic and molecular tools in cell cycle regulation. The UPS pathway in P. falciparum and imaging technology, many exciting discoveries have has been deduced by Dr Hagai Ginsburg been made in the biology of growth and development of (http://sites.huji.ac.iL/malaria/maps/proteaUbiqpath.html) Plasmodium. Genome sequencing projects have been suc- and is suggested to carry out functions specific to pathogene- cessfully completed for P. falciparum and other species sis or virulence [25]. Recent studies show that pineal hor- [12,13,14]. It is suggested that progression of the malaria mone melatonin up regulates genes related to Ubiq- parasite life cycle involves interplay between the parasite’s uitin/proteosome system which is inhibited by melatonin changing environment and its own built in genetic pro- antagonist luzindole [28]. The effects of melatonin on UPS gramme [15]. Examination of the P. falciparum proteome transcription modulation is mediated by a protein kinase detected more than 900 proteins in gametocytes, and out of known as PfPK7, a P. falciparum orphan kinase that causes these 315 are found exclusively in gametocytes. Nearly 97 increase in cytosolic calcium, and up regulation of UPS proteins identified are gamete specific [16]. The absence of genes [28].The signalling pathways in Plasmodium is fun- sex chromosomes in malarial parasites and the presence of damental to the development of new drugs to control ma- gametocyte specific and sex specific genes found dispersed laria. Nearly 20 to 30% of the drug discovery programme in amongst 14 chromosomes raises many unsolved questions most pharmaceutical companies focuses on protein kinases regarding the molecular mechanism that triggers gameto- [29]. Kinase inhibitors like genistein and tyrphostin block P. genesis of malarial parasites. The only known fact that is falciparum cell cycle [30]. Treatment with melatonin in- understood now is that all merozoites from a sexually com- duced increases in cyclic AMP production and PKA (pho- mitted schizont will become either male or female [17,18]. sophokinase) both in P. falciparum and P. chabaudi (rodent Factors that influence gametocyte development include host malarial parasite) but the increase of cAMP/PKA is high in RBC age, hypoxia, and other factors [7]. The first molecular P. chabaudi [31]. markers of gametocytes namely Pfs16 and Pfg27/25 are expressed within 24 hrs after their commitment and differentia- MALARIA ERADICATION PROGRAMMES tion of sexual stages at cellular level [7]. Some studies sug- Although global malarial eradication programme gest potential signalling pathways in the parasite as essential launched by WHO in 1955 has been effective [32] in eradi- in triggering gametocytogenesis. Both phorbol ester inducing cating malaria, more people are at risk of suffering from ma- pathways [19] and the cAMP signalling pathway [20] are laria now than at any other time [33]. It is estimated that implicated. It is suggested that G-protein dependent signal- more than 2 billion people are at risk of suffering from ma- ling system may mediate the switch to sexual development laria [34]. Hence there is urgent need for effective imple- in response to environmental factors [15]. mentation of global fight through multifaceted approach to control malaria. The use of vector control programmes like INTRA ERYTHROCYTIC PHASE OF PLASMODIUM spraying with DDT (dichloro-diphenyl-trichloroethane), in- FALCIPARUM secticide impregnated bed nets to protect against infection by The intra erythrocytic phase is the most lethal form of mosquitos, and medicines to treat both infection and for pre- human malarial parasite and it is the primary cause of ma- vention are some of the suggested methods [33]. The need to laria morbidity and mortality. Arrest of the RBC stage of develop effective human malaria vaccine will be helpful not Plasmodium life cycle is considered as the main pharmaceu- only to serve those living in malaria endemic areas and also tical target [21]. The RBC cycle of P. falciparum occurs over eradicating the disease at the global level [35]. The first vac- a period of 48 hrs and consists of three stages of develop- cine developed by Glaxo Smith and Kline (GSK) RTSS has ment known as ring, trophozoite, and schizont,which give been effective in reducing the risk of Clinical Malaria and in rise to number of merozoites that are released into circulation preventing of episodes of severe malaria for at least 18 at the specific time of the day [22,23]. Evidences support the months [36]. But serious doubts have been raised over long- role of host circadian system and the pineal hormone mela- term prophylaxis by vaccination since malarial parasites de- Malaria, Anti Malarial Drugs and the Role of Melatonin Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 5 373 velop various sophisticated mechanisms to avoid the host showing the action of anti-malarial drugs are shown in (Fig. immune system [33]. With this in mind Bill and Melinda 1). gates foundation (2007) introduced an agenda with the final goal of eradicating malaria that is to extinct all species of TRANSMISSION BLOCKING DRUGS (TBD) Plasmodium that cause malaria infection in man [37]. Be- sides the four Plasmodium species that cause malaria in hu- Eradicating malaria also depends on medicines that pre- mans, a fifth species known as Plasmodium knowlesi origi- vent transmission of parasite between humans and mosqui- nally described as a parasite of long tailed macaque monkeys toes. Reduction of gametocytes in their mature forms (stage- also infects humans in some areas of Malaysia [38]. Unlike V) should be the key targets for tansmission-blocking drugs. other Plasmodium species P. knowlesi malaria has a daily Clinical studies have shown that primaquine eliminates ga- replication cycle and when not treated it will reach poten- metocytes effectively when used alone [50] or when com- tially lethal levels of parasitemia [39]. A recent prospective bined with sulphadoxine-pyrimethamine and artesuanate clinical study conducted in the Sarawak region of Malaysia, [51]. The most severe “bottleneck” identified during the reveals that approximately 10% of the patients infected with process of transmission from the mature gametocyte in the P. knowlesi had severe signs and symptoms and 1-2% of human host through gametogenesis and fertilization in the cases have a fatal outcome [40]. All lethal cases of P. mosquito blood is the oocyte in the mosquito haemocoele, knowlesi developed prominent abdominal signs and symp- which is the main target for drug intervention. P. berghei toms, associated with kidney liver dysfunction with concur- ookinate production in vitro was identified as the most prac- rent hyperparasitemia [41]. Besides Sarawak, cases of P. tical approach for identifying the molecules that target the knowlesi are now reported throughout Peninsular Malaysia early development of Plasmodium parasites in the mosquito. and the cases are increasing year after year [42]. The vector Of the forty six molecules tested at a concentration of 10M, that transmits P. knowlesi is Anopheles Cracens [43]. Thera- the most potent molecules identified were cyclohexamide, peutic procedures using chloroquine was found effective in and atovaquone [49]. Drugs like thiostrepton and pyro- treating patients with P. knowlesi infections [44]. naridine although less effect in inhibiting ookinate production, inhibited P. falciparum exflagellation by more than 80% like sulfamethaxazole and mefloquine [49]. Although ANTI MALARIAL DRUGS the design of drugs that act on ookinate are attractive, it re- The four principal purposes for which anti malarial drug quires a compound that has half life that matches with that of therapy should be used are (1) to treat malaria illness (2) to gametocytes. While this is possible with majority of malaria prevent infection and disease caused by malaria (3) to elimi- species (with gametocytes with short 1-2 days half life), it is nate dormant malaria parasites from the liver and (4) to pre- difficult with P. falciparum where mature gametocytes sur- vent malaria transmission [8]. Successful malaria control and vive up to three weeks. Moreover targeting oocyte with elimination programmes depends mainly upon the use of drugs or vaccines will be more difficult because exposure of treatment and prevention procedures based on drugs rather oocytes to drugs and selective delivery of drugs to oocytes is than use of insecticides carried out in the mid 20th century. impossible to control and will result in the development of Priority should be given to the use new innovative anti ma- drug resistance only [7]. larial drugs that can replace drugs loosing efficacy due to the advent of resistant parasites [8]. Speed of action is consid- MELATONIN BIOSYNTHESIS AND REGULATION ered as one of the main determinant of anti malarial compound efficacy and is also a “crucial clinical parameter” to Melatonin is the neurohormone secreted mainly by the determine the in vivo PCT [2]. The fasted drug tested is pineal gland of all vertebrates and is also synthesized by artemisinin with an immediate onset of action with an in many other tissues and organs in the body (Fig. 2). Lympho- vitro PRR higher than 8.0. Of the various anti malarial com- cytes [52], thymus [53], gastrointestinal tract [54], skin [55], pounds tested mefloquine, chloroquine, artemisinin, and are some of the organs that synthesize melatonin. In all these pyrimethamine induced reduction in the number of viable areas, melatonin plays either a paracrine or autocrine role parasites more than 99.9% after 72 hours of treatment. Re- [56]. Biosynthesis of melatonin begins with tryptophan get- duction in viable parasite to virtually zero levels occured at ting converted into 5-hydroxytryptophan which is then de- 72 hours [2]. Drugs like artemisinin and its derivatives arte- carboxylated into 5-hydroxytryptamine or serotonin. Sero- sunate, halofantrine induced greatest and artemether contain tonin is then acetylated to form N-acetyl serotonin by the endoperoxidase bond that is required for anti malarial prop- enzyme arylakylamine-N-acetyl transferase (AAANT). N- erties [45]. Drugs like atavaquone, triazolopyrimidine and acetylserotonin is then converted in to N-acetyl-5-methoxy pyridine directly impair the parasite mitochondrial function tryptamine or melatonin by the enzyme hydroxyl-indole-O- for its antimalarial activity [46]. All endoperoxides whether methyl transferase (HIOMT). High nocturnal activity of ary- natural, semi-synthetic or synthetic (artemisinin, DHA, arte- lakylamine-N-acetyl transferase, correlating with melatonin suanate, OZ 277, OZ439) are the most potent anti malarials activity occurs in the pineal gland of rats [57]. Pineal mela- that are currently used against asexual blood stages and they tonin biosynthesis is regulated by the suprachiasmatic nu- act by alkylating haem and other vital biomolecules [45,47] cleus (SCN) of the hypothalamus and is entrained to light- and by degrading phospholipids in parasite membranes [48]. dark cycle through retino-hypothalamic tract [58]. Special This later action of endoperoxides has a major impact on all melanopsin containing ganglion cells (RGS) of the retina replicating stages of Plasmodium life cycle like asexual [59] convey the light-dark cycle information to SCN of the blood stage, liver schizont, oocyst, and microgametogenesis hypothalamus. The SCN then projects to a circuitous neu- and these have been demonstrated [49]. Schematic diagram ronal network in the hypothalamus, median forebrain bundle 374 Infectious Disorders – Drug Targets, 2012, Vo l. 12, No. 5 Srinivasan et al.

Plasma

Melatonin

Luzindole

G-Coupled MT1/MT2 Melatonin Receptors

Ubiquitin/ Serpentine Receptors

Proteosomal

Signaling path way

Phospholipase C Activation Anti kinases Genistein tryphostin

Inosital Tri Phosphate IP3 Artemisinin Luzindolee

2-APB +2 (2-amino ethyl Intra cellular release of Ca

diphenyl borinate) from ER

Atavaquone & artemisinin Increased Growth and endoperoxidases, Differentiation of Plasmodium triazolopyrimidine impair Increase of Mature forms, mitochondrial Schizonts function of malarial parasites Some

Luzindole (Melatonin receptor blocking drug)

Blocks

Stimulates

Fig. (1). Malarial parasite growth and development and mechanism of action of some anti-malarial drugs. and reticular formation of the medulla to reach ultimately the its cyclic AMP signal transduction cascade when acts intermedio lateral horn cells of the high thoracic region of through these systems [65]. However in COS-7 transfected the spinal cord which constitute the preganglionic neurons cells with cloned MT1 receptors and in human neuroblas- that innervate the superior cervical ganglion (SCG) [58]. toma cells SH-SY5Y, melatonin causes stimulation of cyclic Post ganglionic fibers arise from the SCG and innervate the AMP [66]. MT2 receptor couples to a number of signal pineal gland and regulate melatonin synthesis by releasing transduction pathways causing phospho inositide production, norepinephrine (NE) at its nerve endings. NE released from inhibition of adenyl cyclase and inhibition of guanylyl cy- the postganglionic nerve fibres activates adenyl cyclase cyclase pathway [67]. The action of melatonin on both MT1 clic AMP pathway of pinealocyte and induces expression of and MT2 receptors is blocked by a common melatonin re- biosynthetic enzymes involved in melatonin formation in the ceptor antagonist luzindole [68]. With regard to MT2 mela- pineal gland [60]. Once formed melatonin is not stored in the tonin receptors multiple signalling has been reported. For pineal gland but diffuses out directly into the blood or cere- example, in the rat SCN, MT2 activation causes not only brospinal fluid [61]. decrease of cyclic AMP but also increase in the levels of protein kinase C (PKC) which was specifically blocked by MELATONIN RECEPTORS MT2 receptor selective antagonist, 4-phenyl-2-propionami- dotetraline (4-P-PDOT) [69,70]. Activation of phospholipase Melatonin exerts its effects on various cells and tissues of C by melatonin results in increases of inositol-1,4-5-tris the body by acting through membrane bound MT1 and MT2 phosphate (IP3) and this has been demonstrated by using melatonin receptors [62,63]. Both MT1 and MT2 melatonin insulinoma INS1 [71,72]. The fact that occurrence of mela- are G-protein coupled receptors [64]. MT1 melatonin recep- tonin is not restricted to vertebrates but is ubiquitously dis- tor activation leads to stimulation of large variety of G- tributed in numerous taxa including bacteria, unicellular eu- proteins like Gi2, Gi3 and Gq [65]. Melatonin mostly inhib- karyocytes [73,74,75]. Melatonin displays multiplicity of Malaria, Anti Malarial Drugs and the Role of Melatonin Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 5 375 actions and displays integrative, orchestrating role not dis- role in melatonin transduction pathway. Melatonin modify played by many other signal molecules. The distribution of the life cycle of P. falciparum by up regulating the genes its receptors and other binding sites in various cells and tis- related to ubiquitin/proteosomal system and ample evidences sues as well as in unicellular organisms indicates a remark- have been documented for involvement of melatonin in regu- able pleiotropy of melatonin [76]. lating ubiquin-proteosomal system and signalling pathways in Plasmodium [28]. This effect of melatonin on ubiquitin- proteosomal syatem was completely blocked by melatonin Tryptophan antagonist luzindole showing thereby the presence of melatonin receptors on the surface of Plasmodium membrane and their involvement in mediating melatonin’s modulatory ac- TRYPTOPHAN-5-HYDROXYLASE tion on Plasmodium’s growth and development [28]. Not only melatonin but its precursors N-acetylserotonin, tryptamine, serotonin, and melatonin’s metabolite N(1)-acetyl 5-hydroxytryptophan N(2)-formyl -5-methoxykynuramine (AFMK) also modulate (5HTP) the intra erythrocytic P. falciparum cell cycle [78,79]. The ability of melatonin and other tryptophan derivatives to synchronize P. falciparum cultures were blocked by inhibition 5-HTP-DECARBOXYLASE of PLC and melatonin receptors [78,79]. Moreover the effects of melatonin on Ca2+ release and synchronized progres- 5-hydroxytryptamine sion through the cell cycle are blocked by phospholipase C (Serotonin) (PLC) inhibitor U73122 [78,79]. As has been pointed out in the earlier paragraph, melatonin increases both cAMP and 2+ ARYLALKYLAMINE N-ACETYLTRANSFERASE PLC that causes Ca mobilization and this action of mela- (NAT OR AANAT) tonin is essential for synchronization of malarial parasite’s cell cycle [80]. Thus the existence of classical PLC depend- 2+ N-acetyl-serotonin ent intracellular Ca release pathway in P. falciparum and (NAS) its stimulation by melatonin has been shown to be the main mechanism for parasitic development and release in the hu- Acetyl serotonin methyl transferase man host [81]. (ASMT) MELATONIN’S INVOLVEMENT IN OTHER PARA- Melatonin SITES

(N-acetyl-5-methoxytryptamine) In unicellular organisms melatonin is invariably associated with night time and functions mainly as a “darkness signal” [82]. Trypnasoma cruzi, (a parasite) synthesizes and responds to melatonin, and the hormone melatonin is essen- Fig. (2). Melatonin biosynthesis. tial for regulating its life cycle and for its parasitic ability [74]. Similarly in another unicellular parasite, namely a, MELATONIN’S MODULATION OF MALARIA nematode Caenorhabditis elegans, an endogenous circadian PARASITE REPLICATION CYCLE pacemaker has been described [83,84]. In this species mela- Melatonin’s involvement in modulating the life cycle of tonin seems to act as a neuromodulator regulating locomotor Plasmodium falciparum has been the subject of investigation activity and also regulates its activity through distinct recep- for long time. In vitro studies of incubating malarial parasites tor pathway [85]. It is suggested that microfilaria, Wuchere- with different doses of melatonin ranging from 10-100 nM ria bancrofti that are released into the host’s blood during and examination of different stages of malarial parasites night time, is cued by the host secretion of melatonin [86]. showed reduction in the percentage of cells of ring and tro- From these examples it is clear that these organisms have phozoite stage but increase of mature schizont stage (two endogenous circadian rhythms that are self sustained but times higher) [9]. As host melatonin secretion is high during synchronized to the 24-hour day by environmental time cue dark hours of the night, it was inferred that host melatonin and that is melatonin [86]. secretion occurring at night time (melatonin secretion begins at around 7.00PM to 9.00PM and reaches maximum around THERAPEUTIC INTERVENTIONS AGAINST 2.00AM to 4.00AM) act to synchronize the Plasmodium cell MELATONIN’S ACTIONS ON P. FALCIPARUM cycle. The increase of parasitemia caused by melatonin was From the forgoing discussions on melatonin’s effects in completely abolished by melatonin receptor antagonist luz- modulating P. falciparum replication cycle it is evident that indole and from this it was concluded that “host-derived sig- inhibition or suppression of nocturnal melatonin secretion in nal” for release of billions of malarial parasites into the the host or prevention of melatonin’s action on Plasmodium blood is melatonin [9]. Recent genome analytical studies falciparum by way of using melatonin receptor antagonists showed that both calcium and cyclic AMP are essential for or agents that inhibit PLC activation in malarial parasites can co-ordinating the events of maturation and development of help to prevent the development of later asexual stages of intra erythrocytic stages of Plasmodium [77]. A protein Plasmodium [87]. Luzindole, the common MT1 and MT2 kinase PfPK7 a P. falciparum orphan kinase plays crucial 376 Infectious Disorders – Drug Targets, 2012, Vo l. 12, No. 5 Srinivasan et al. melatonin receptor antagonist can be employed to prevent programmes [7]. The endoperoxides, whether natural or syn- the development of asexual stages of malarial parasites in thetic (artemisinin, or its derivatives dihyroartemisinin) are man. Luzindole can be administered to the host at late eve- the most potent anti-malarial drugs that are currently used ning around 6.00PM and blood can be examined for the against asexual blood stages [45]. Although the design of presence of asexual stages of malarial parasites namely drugs that act on ookinate are attractive but will be difficult Plasmodium falciparum or Plasmodium knowlesi through to achieve because it requires a compound that has half life serial blood samples drawn during night (every two hours or that matches with that of gametocytes [7]. Recent studies three hours). Once the complete elimination of asexual have shown that melatonin secreted at night time synchro- stages of Plasmodium in the host’s blood is confirmed, the nizes the Plasmodium cell cycle. Both intracellular calcium drug (luzindole) can be administered for duration of one and cyclic AMP are essential for co-ordinating the events of month. The dose and the number of days to be administered maturation and development of intra erythrocytic stages of have to be worked out only after conducting pilot study on Plasmodium [77]. Melatonin by acting on cAMP and intra- malaria infected patients (Plasmodium falciparum or Plas- cellular Ca2+ release regulates Plasmodium cell cycle [81]. modium knowlesi). To compensate for the melatonin defi- Hence use of drugs that block the action of melatonin on ciency induced in the host by luzindole at night, melatonin at Plasmodium or the procedures like bright light that can sup- physiological doses (0.25mg to 0.5mg) can be administered press the nocturnal plasma levels of melatonin completely during daytime for the entire period of treatment with mela- will be effective methods for arresting the growth and devel- tonin receptor antagonist. opment of asexual stages of malarial parasite growth and development [87]. Melatonin the hormone released from the MELATONIN ANTAGONISM: BRIGHT LIGHT AP- pineal gland is an effective anti oxidant, that has been shown PLICATION to be effective in preventing oxidative stress induced hepatic damage and apoptosis seen in Swiss mice infected with ma- Exposure to bright light during night time causes either larial parasites [94]. But the beneficial effects of melatonin reduction in plasma melatonin levels or complete suppres- in malaria infected animal species [95] cannot be applied to sion of plasma melatonin depending upon the intensity of the human cases since in humans, the beneficial actions of mela- light applied. Exposure of human beings to 2500 lux at tonin will be much overshadowed by its action in promoting around 2.00AM caused complete suppression of plasma malarial growth and development. Hence use of melatonin melatonin concentration [88]. As circadian changes of antagonists or the procedures that suppress plasma melatonin plasma levels of the host constitute a key signal that causes levels completely will only be helpful in preventing growth synchronous maturation and development of Plasmodium [9] and spread of malarial infections caused by Plasmodium and malarial parasites have intrinsic ability to sense plasma falciparum, Plasmodium malariae, or Plasmodium knowlesi melatonin levels [81], complete suppression of plasma mela- infection in human beings. tonin at night can be helpful in desynchronizing plasmodium growth and development and arrest the parasitic cell cycle CONFLICT OF INTEREST and development of gametocytes in the host [87]. A light mask treatment, using light applied through eyelids during V. Srinivasan is the Founder chairman of Sri Sathya Sai sleep will deliver light intensities of required intensities Medical Educational and Research Foundation, Kovai thi- without affecting patient’s sleep at night [89]. Patency for runagar, Coimbatore-641014, Tamilnadu, India. He declares delivering bright light through eye lids has recently been no competing interest that might be perceived to influence approved US 2012/0041520A1 [90]. the contents of this paper. All other authors of this review paper also declare that they have no proprietary, or any other CURRENT AND FUTURE DEVELOPMENTS type of personal interest of any kind in any product or serv- ices and/or company that could be construed or considered Human malaria is caused mainly by infection with Plas- as a potential conflict of interest that might have influenced modium falciparum, and Plasmodium malariae [91]. Now the views expressed in this review paper. 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Received: April 26, 2012 Revised: August 27, 2012 Accepted: August 27, 2012