REVIEW Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Al Qassim, Kingdom of Saudi Arabia Candidate mechanisms of caffeine improving memory dysfunction A. ALHOWAIL Received August 1, 2019; accepted August 30, 2019 Ahmad Alhowail, Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, 51452 Al Qassim, Kingdom of Saudi Arabia [email protected] Pharmazie 74: 705-710 (2019) doi: 10.1691/ph.2019.9711 Caffeine is the most common psycho-stimulant that is broadly known to cause peripheral effects. Caffeine is well known as an adenosine receptor antagonist. Adenosine receptors are present in all areas of the brain, which makes caffeine’s effects very prevalent. The main goal of this review is to summarize recent studies that are investigating the mechanism of action of acute and chronic caffeine treatment of to alleviate the cognitive deficits and synaptic plasticity. This review discusses the effect of caffeine on the brain functions including learning and memory, and synaptic plasticity in case of various diseases. 1. Introduction world’s most abundantly consumed psychoactive drug. It is chem- Caffeine has been used for centuries and it is suggested that it ically 1,3,7-trimethylpurine-2,6-dione with molecular formula enhances various central nervous system (CNS) functions, but C8H10N4O2 and correlated to the adenine and guanine nitrogen the exact mechanism is still elusive. Caffeine is contained in bases of deoxyribonucleic acid and ribonucleic acid. Due to the many beverages such as coffee, tea, and soft drinks. Many people absence of stereogenic centers, caffeine is identified as an achiral o intend to drink coffee or tea to consume caffeine, believing that it molecule (Fig. 1). It is weakly basic (pKa of 10.4 at 40 at 25 C increases cognitive function, attention, and alertness. Studies have (Rodopoulos et al. 1995). shown that two hours after consuming coffee the caffeine concen- Caffeine is regarded to have many different effects like memory tration reaches the peak levels (Carrillo and Benitez 2000), causing enhancing (Borota et al. 2014; Cunha and Agostinho 2010), anti- several effects such as increasing blood pressure (Mesas et al. cancer (Tomita and Tsuchiya 1989), and antioxidant effects (Azam 2011), and dopamine, glutamate (Solinas et al. 2002), epinephrine, et al. 2003). It is lipophilic in nature and this property allows for norepinephrine, and cortisone levels (Lovallo et al. 2005; Minana rapid absorption into the bloodstream where it freely crosses the and Grisolia 1986). blood-brain barrier (BBB) (Alzoubi et al. 2013). In this review, Caffeine is used as a CNS stimulant and plays a vital role in learning most recent studies on caffeine, linked to the effect of memory and memory modulation. Studies revealed that caffeine enhanced function such as behavioral tests, electrophysiological assessment, the cognitive function in both clinical and experimental studies and molecular signaling are discussed as a potential therapy for (Cunha and Agostinho 2010; Han et al. 2013). Furthermore, the some disease conditions. administration of caffeine improved memory impairment caused by multiple brain disorders and diseases such as Alzheimer’s 2. Caffeine and synaptic transmission disease (AD), Parkinson’s disease (PD) and sleep deprivation (Alkadhi et al. 2013; Han et al. 2013; Roshan et al. 2016). At the synaptic level, caffeine is found to be a competitive blocker Caffeine belongs to methylxanthine class which mainly acts as for adenosine receptors, mainly A1 and A2A subtypes (Biaggioni et central nervous system (CNS) stimulant (Nehlig et al. 1992). It is al. 1991; Costenla et al. 2010). Once caffeine blocks the adenosine a white crystalline purine, a methylxanthine alkaloid which is the receptors, this action leads to increase in the release of other neurotransmitters such as dopamine, noradrenalin, and glutamate (Solinas et al. 2002). Thus, these neurotransmitters are highly expressed in the brain and this in turn will play an important role in regulating memory processes (Myhrer 2003). Several lines of evidence showed that a reduction in dopamine, noradrenaline, and glutamate levels results in cognitive deficits (Coradazzi et al. 2016; Diggs-Andrews et al. 2013; Merritt et al. 2013). Caffeine blocks adenosine receptors, and increases the levels of other neurotrans- mitters in the synapse. Electrophysiology is a technique, which is used to mimic the physi- ological function of tissues or cells. The major electrophysiological test that is used to evaluate memory function in the synaptic level is long-term potentiation (LTP), which measures memory at cellular level (Bliss and Collingridge 1993). This test mainly evaluates the strength of neuronal communication, particularly synaptic strength and weakening (Chang et al. 1999). Electrophysiological studies using LTP have shown that cognitive dysfunction is associated with some neurological disorders and diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and sleep deprivation (Alkadhi et al. 2013; Chiaravalloti et al. 2014; Jahn 2013). Interest- Fig.: Chemical structure of caffeine ingly, chronic caffeine treatment revealed to rescue the LTP in many Pharmazie 74 (2019) 705 REVIEW neurological disorders. For instance, sleep deprivation, AD, and PD (Sherer et al. 2012). This disease is affecting approximately 1% of caused a decrease in LTP and the research findings revealed that population with age more than 60 years (Bezard et al. 2001). Patho- caffeine can improve the reduction in the LTP and memory function. logically, this disease is characterized by selective dopaminergic neuronal degeneration in the substantia nigra of the midbrain and 3. Caffeine and stress the development of neuronal Lewy Bodies. PD is associated with risk factors including aging, family history, pesticide exposure Chronic exposure to stress increases stress hormones, which may and environmental chemicals. However, the exact cause of PD cause several problems to the body including the brain (Magarinos is still unclear and is characterized by both motor and non-motor et al. 1997). Likewise, studies have shown that acute caffeine system manifestations. PD could associate with neurobehavioral consumption leads to elevate cortisol levels (Lovallo et al. 2005). disorders such as depression, anxiety, cognitive impairment, and Severe and long-term increase of stress hormones can change autonomic dysfunction. Studies have reported that correcting the normal brain structure and function and these changes might result dopamine deficiency in PD with levodopa (L-dopa) significantly in cognitive impairment (Magarinos et al. 1997; McEwen et al. attenuates the motor symptoms (Guttman 1992). However, defini- 1997). In experimental animals, stress alters protein expression tive disease-modifying therapy is still lacking. The diagnosis of PD and functions of proteins such as BDNF and CaMKII (Gerges et is based on the symptom signs such as rigidity, bradykinesia, and al. 2004; Mondelli et al. 2011; Murakami et al. 2005) that affects tremors as well as cognitive impairment (Ng 1996), and it initiates memory function. Nevertheless, chronic treatment with caffeine in the loss or degeneration of the dopaminergic neurons (dopa- rescues the cognitive impairment and elevates the expression of mine-producing) in the substantia nigra (Barber et al. 2001). This BDNF and CaMKII proteins, which are reduced by stress and loss of dopamine producing neurons leads to impairment of motor sleep deprivation in the hippocampus (Alzoubi et al. 2013). There- control and memory function (Kinoshita et al. 2015). Besides fore, caffeine is acting against the effect of stress in the brain by causing motor symptoms, PD (Braak et al. 2003) is involved in reducing the side effects caused by the of stress. non-motor symptoms such as cognitive impairment (Aarsland et al. 2012). Preclinical studies have revealed that caffeine has 4. Caffeine and CNS disorders improved both motor and non-motor symptoms of PD patients through synergetic effect between the adenosine and dopamine CNS disorders, including neurodegenerative disease such as AD and PD are characterized by primary alteration in brain function causing receptors (Manalo and Medina 2018). Thus, caffeine may repre- cognitive impairment (Jahn 2013; Leverenz et al. 2009). Generally, sent as a promising preventive strategy for cognitive impairment AD and PD are found to develop neurodegeneration by increasing associated with PD. pro-apoptotic markers (Yalcinkaya et al. 2016; Ye and Fortini 1999). Contrarily, caffeine acts to decrease the pro-apoptotic and increased 4.3. Caffeine and attention defi cit hyperactivity disorder the anti-apoptotic markers, which ultimately increases the survival (ADHD) rate of cells (Blandini et al. 2003; Zeitlin et al. 2011). ADHD is a neurodevelopmental disorder affecting subjects of all age groups. ADHD patients could have difficulty preserving 4.1. Alzheimer’s disease (AD) attention or they may exhibit some hyperactivity that affect AD is a common neurodegenerative disease in elderly people causing their daily life of children such as school performance (Loe and dementia, and is characterized by deposition of β-amyloid (Aβ) and Feldman 2007). These symptoms commences around the age of tau protein in the brain. Aβ oligomers and plaques are considered seven years in between 4 to 12% of students in the world and it potent neurotoxins. Accumulation of β-amyloid inhibits mitochondrial lasts for