Annals of Neurosciences, Vol 16, No 3 (2009)
Annals of Neurosciences, Volume 16, Number 3, July 2009
Memory - mechanisms, tools and aids
ABSTRACT
Memory loss is an abnormal degree of forgetfulness and inability to retrieve past experiences and events. Nootropic agents act on brain to improve the cognitive function. They are used for the treatment of amnesia or dementia, occurring due to the disturbance of neuronal mechanism in various pathological conditions. Long-term potentiation (LTP) is a well-accepted molecular mechanism of learning and memory. Neurotransmitters such as GABA, Nor-epinephrine, dopamine, acetylcholine etc and their receptors are also reported to modulate learning and memory. Impairment in the physiological process of LTP produces memory deficits. Moreover, antioxidant, metabolic enhancers, chelators, nerve growth factors and calcium channel blockers have been reported to decline the progress of neurodegeneration and improve the cognition. Drugs, obtained from various plant sources, are now tested in animals and humans with hope of inventing newer therapeutic agents.
KEYWORDS: Amnesia, Bacopa monniera, Long term potentiation. Herbal drug.
Corresponding Author: Manish Saraf, E-mail: manishsaraf123@rediffmail.com
doi: 10.5214/ans.0972.7531.2009.160308
Introduction
Memory loss has multiple causes including chronic medical and psychological conditions, trauma, medications and drug or alcohol abuse. Dementia is one of the causes of memory loss which is defined as an acquired loss of cognitive, emotional and intellectual abilities severe enough to interfere with occupational functioning, social activities and relationships. Dementia affects around 7% of the general population older than 65 years which doubles every five years, to reach 30 to 50 % by the age of 85. The causes of dementia include Alzheimer’s disease, vascular dementias, dementia with Lewy bodies, fronto-temporal dementia etc. Fortunately, basic research during the past 25 years has begun to define a chemistry of brain plasticity, which is suggesting new gene targets for the discovery of memory enhancers and antiamnesic agents. Cognition enhancers attenuate some aspect of brain dysfunction. Many such enhancers have been found, and their actions tend to involve interactions between neurohumoral signalling responses and the cholinergic system. To date, only one class i.e. cholinesterase inhibitors has been approved for the treatment of Alzheimer’s disease. Marketed drugs such as Donzepil, Rivastigmine and Galantamine, all cholinesterase inhibitors, yield mild improvement in the progressive memory loss in AD patients, but their ameliorating effects are variable and transient. Scientific research has begun to identify the molecular biology of memory formation and has shown that the ability to form memories is based on neuronal ‘plasticity’. This is generating new gene targets, drug screens, chemical compounds and preclinical data to suggest drug classes capable of directly enhancing the memory process. In essence, rush is on to identify genes involved in memory formation and to then discover drug compounds that can modulate memory by interacting with the protein products of these genes. This effort promises to provide effective therapies for the treatment of various forms of memory loss associated with heredity, disease, injury or age. On the other hand, the traditional knowledge of herbs and extracts is also available in various combinations, and is being scientifically validated for memory improvement in human beings.
Long term potentiation : Physiological basis of learning and memory
Brain is evolutionary designed to sense its internal and external environment and to perceive causal relations among stimuli as well as to change its response adaptively. To accomplish this incredible task, a self-regulating network of 40,000 genes directs the development of a cellular network of 100 billion neurons with 7 trillion connections among them. The coordinated activity between presynaptic and postsynaptic neurons is essential for synaptic strengthening. The synaptic strengthening is a consequence of coordinated activity between presynaptic and postsynaptic neurons. Brain stores the information by changing the efficacy of synapses in the way of synaptic strengthening. The emergence of long term potentiation (LTP) as a widely accepted physiological mechanism of memory has revolutionised the field. It is referred as a persistent increase in amplitude of EPSP and consequently prolonging of synaptic transmission in certain neurons of the hippocampus. Brief high frequency stimulation of afferent fibers of hippocampus neurons induces LTP. Such stimulation release glutamate from presynaptic neurons and activate postsynaptic glutamate receptors such as AMPA receptor1, NMDA receptors2 and metabotropic receptors. Persistent activation of AMPA receptors by glutamate produces sufficient postsynaptic depolarization to overcome Mg++blockage and allow influx of Ca++ion through pore of NMDA receptors. Among the immediate effects of Ca2+ are the activation of CaMKII, PKC, tyrosin kinase and calcineurin. Ca-calmodulin kinase phosphorylates non-NMDA channels, increasing their sensitivity to glutamate. Ca++/Calmodulin complex also activates nitric oxide synthetase to form nitric oxide. The backward diffusion of several endogenous substances formed in postsynaptic neurons such as nitric oxide. Carbon monoxide, arachidonic acid, platelet activating factor are also formed in postsynaptic neurons and act as retrograde messengers. These retrograde messengers activate presynaptic neurons to release neurotransmitters such as glutamate. Long-lasting LTP occurs when adenylyl cyclase is activated by Ca2+ or by modulatory inputs such as dopamine or serotonin (5-HT), which stimulate adenylyl cyclase through G-protein-coupled receptors. This leads to increases in cAMP levels, which activates PKA, which then translocates into the nucleus where it phosphorylates CREB, thereby triggering of transcription of CRE (cAMP response element) factors leading to translation of various genes which elicits formation of various effectors such as tissue plasminogen activator (tPA), brain-derived neurotrophic factor (BDNF) and regulators such as CCAAT enhancer binding protein (C/EBP). Other protein kinases such as CaMKII, CaMKIV and MAP kinase also regulate gene expression. Ras-GTP and protein kinase-Α subsequently activates MAPK/ERK (mitogen activated protein kinase / extracellular regulated kinase) cascade system to generate retrograde signals and to increase the expression of immediate early response (IER) gene and late response (LR) genes, responsible for short term and long term memory respectively. Rac and Raf, as component of Ras signaling system, activate transcription of JUN by activation of stress activated protein kinases (SAPKs) and ternary complex factor (TCF) through activation of MAPKs. MAPKs is translocated to nucleus to activate two parallel signaling pathway in ’fos’ promoter i.e. MAPK/ERK-TCF pathway targeting serum response element (SRE) and MAPtyERK-CREB pathway targeting cAMP response element (CRE). JNK and p38 phosphosylate activating factor transcription element-2 (ATF-2).JNKsalso phosphorylate c-JUN. A heterodimer consisting of c-Jun and ATF-2 activates AP1 site in the c-jun promoter and consequently increase the expression of c-jun. The final result of the concerted activity of these transcription modulators is to increase the concentration of Jun-Fos dimer, which will activate a unknown target gene and will bring alteration in synaptic structure and will induce formation of new synapses. Induction of LR gene modulates the formation of various enzyme proteins responsible for the development of long-term memory. Activation of postsynaptic PKC has been reported to activate silent AMPA receptors. The calmodulin kinase II translocates to the postsynaptic density (PSD) and interacts with Ν Μ DA receptors to prolong their activated state.
It is now understood that there is extensive crosstalk among these different kinase pathways. CREB pathay is believed to dominate process of synapse formation. Many scientists believe that the formation of new synapses is implied with long-term memory process. The emergence of novel concept of molecular and cellular mechanism of memory coupled with rapidly expanding information about molecular biology of synaptic plasticity has resulted in a new effort to invent mechanism based memory drugs.
Memory disorders and management
Dementia can be diagnosed by observing three essential features i.e. multiple cognitive defect (aphasia, aprexia, agnosia), impairment in occupational/ social functioning, and decline in the previous high level of functioning. The causes of dementia can be identified by laboratory evaluation in which various neurological investigation are performed such as EEG (electroencephalo-graph), brain CT (computed tomo-graphy)/MRI (magnetic resonance energy), nerve biopsy, thyroid profile, vit-B12, CSF (cerebro-spinal fluid), folate, heavy metal and some neurophysiological testing. Various allopathic and herbal preparations are believed to enhance memory in normal individuals, but their clinical effects are limited. Moreover, their clinical and therapeutic efficacy is still controversial. These preparations have been also used to treat primary or secondary dementia in preclinical and clinical cases. Most of the smart drugs/nootropic agent act on brain barrier and subsequently increase brain metabolism and cerebral circulation. Moreover they protect the brain from physical and chemical damage. The smart drug is supposed to work in one of two main ways: either by increasing blood flow to the brain or by boosting the levels of neurotransmitters thought to play a part in learning and memory. Consequently, they not only improve mental function, mental energy, alertness and learning ability but also enhance IQ (intelligence quotient), mental clarity and life span. These drugs enhance learning and memory especially under conditions of disturbed neural metabolism resulting from lack of oxygen and age-declined changes. Many of the nootropic drugs are known for their nontoxic effects, however their detailed pharmacokinetic, pharmacodynamic and toxic studies are needed.
The current therapeutic approaches in dementia are centred around Alzheimer’s disease (AD), which occurs due to the destruction of neurons, especially of the neurons that secrete or utilize the neurotransmitter acetylcholine. The cholinergic activities of these neurons are augmented by administration of cholinergic precursor (choline, lecithin), cholinergic receptor agonists (nicotine, arecoline), choline esterase inhibitors (physiostigmine, rivastigmine, eptastig-mine, tacrine, suronacrine, galantha-mine). Metabolic enhancers (nicergoline, idebenone, indeloxazine) improve mild to moderate amnesia by enhancing cerebral metabolic activity and dilating cerebral vessels. Cerebrolysin, a nerve growth factor, attenuates the cognitive function in AD by increasing survival of cholinergic neurons and preventing the declined activity of acetyl choline esterase and choline acetyl transferase .Anti-inflammatory agents such as indomethacin is reported to slow down the progress of neurodegeneration by reducing the formation of inflammatory modulators (e.g. cytokines). Anionic sulphonate and sulphate is documented to seize the process of amyloidogenesis. Desferro-xime, an aluminum ion chelator is another compound which decreases the progress rate of deterioration of neurons in AD. Where as antioxidant like vit-C, vit- Ε are reported to show protective effects because it reduces formation of free radicals and deactivate the free radicals thereby preventing the neuronal cell death. Piracetam, along with food additives such as choline and acetylcarno-sine also enhance memory in Alzheimer’s patients.1 The drugs, such as propanolol, phenytoin2 or hydergine, which increase cerebral blood flow and diminish hypertension, are expected to improve the performance of energy-starved neurons. The calcium channel blockers also alleviate memory deficits. Moreover, ginseng, a herbal medicine, blocks calcium channels and improves the cognitive function. 5-HT antagonists (Ondansetron, Zacopride), K+ channel blocker (Fempridine, Linopridine), angiotensin converting enzyme inhibitor (Captopril) and benzodiazepine receptor inverse agonist (ZK-93426) modulate the release of acetylcholine and help laboratory animals to learn highly specific tasks.3,4,5 Moreover, a few categories of drugs are under preclinical and clinical investigations such as phosphorylase inhibitors, amyloid precursor protein protease inhibitors, glutamate receptor antagonist, amyloid formation inhibitors etc. Centrophenoxine produces a positive influence on the cell metabolism and the mitotic cell division capacity by inhibiting the accumulation of lipofuscin and increasing the antioxidant enzymes and thereby delaying the cellular aging of neurons. Piracetam or nootropyl enhances learning and memory especially under conditions of hypoxia. The effect of piracetam can be increased if taken with DMAE (dimehtylaminoethanol), centrophenoxine, choline, or hydergine. Aniracetam, oxiracetam and pramicetam are the newer derivatives of paracetam. Vinopocetin is more effective in age associated dementia. Because it is known to improve blood flow to the brain, making easier to use glucose and oxygen, and allows the brain to survive longer and better after the periods of oxygen deprivation. It is generally very safe. Ergot derived smart drugs (hydergine, bromocriptine, nicergoline) dilate the blood vessels and help to stabilize brain oxygen levels, if they are too high or if oxygen levels are too low they improve them, and consequently prevent the neural damage due to oxygen derived free radicals. They are used as adjunct to treat age related mental decline but it causes mild nausea, gastric disturbance and bradycardia. Xanthinol nicotinate, a form of niacin, shows a remarkable improvement in short-term and long-term memory in young, middle age and elderly people by increasing the glucose metabolism and corresponding ATP production. But it may cause flushing or a sense of warmth, postural hypotension, heart palpitations, nausea, vomiting, heartburn, diarrhea, headache, muscle cramps and blurred vision. DMAE (dimethylaminoethanol), a demethylated choline molecule, is another agent which reported to elevate mood, improve learning memory and increase intelligence.
Bacopa monniera: Potential aid
B. monniera (Brahmi) is a popular drug used by alternative medicine pratictioners in India. Its medicinal efficacy, reported in Indian traditional literature such as Athar-Ved, Carak Samhita, Susrutu Samhita , is well proven by scientific studies in animal and human. In addition to antiamnesic effect, it exerts antioxidant, antistress, anxiolytic, memory enhancing and antiulcerogenic activities. The preliminary study evaluated that B. monniera alcoholic extract increased the learning ability of rats. Subsequent studies indicated that cognition-facilitating effect of standardized extract of B. monniera was due to two prominent constituents, bacoside-A and bacoside-B . B. monniera also exhibited antioxidant, antistress and anxiolytic activities in animals. B. monniera along with ginkgo biloba extract exerts significant anticholinesterase and antidementic properties in mice and attenuates the scopolamine induced cognition deficit in passive avoidance test exhibiting cholinergic characteristics. Sarab et al.3 has reported that B. monniera significantly reverses diazepam, scopolamine and L-NNA induced amnesia but it does not attenuate MK801 induced amnesia in mice using Morris water maze tests testifying the potential of this herbs in allevating amnesia. B. monniera reverses the scopolamine induced amnesia by significantly improving calmodulin and by partially attenuating protein kinase C and pCREB . B. monniera has also been shown to increase calmodulin (CaM) and pCREB/CREB ratio when L-NNA is used as amnesic agent. There are reports to show that B. monniera alleviates the SOD activity when it is administered with diazepam. B. monniera also provides protection from phenytoin (an antiepileptic drug) induced deficit in cognitive function of mice. Bacosides, the prominent constituent of B. monniera, have been reported to alleviate the amnesic effects of scopolamine. However, there are also reports where it is shown to improve the cognitive deficit possibly by exhibiting free radical scavenging and anti-lipid peroxidative effects that protect the brain from oxidative damage, and by augmenting the anti-oxidative defence system of glutathione, vitamin C, vitamin E, and vitamin A and the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and glutathione reductase (GR) besides maintaining the levels of trace elements such as copper, iron, zinc and selenium. B. monniera extract also reduces the level of amyloid especially Abeta 1-40 and 1-42 in doubly transgenic mouse model of rapid amyloid deposition and reverses Y-maze performance and open field hyperloco-motion behavioral changes . Like animal studies, the clinical studies also provide equally robust evidence of B. monniera’s action on cognitive function. In a clinical study Sharma era/ reported B. monniera’s effect on revitalizing the intellectual functions of children. Some studies have suggested that the choice of dose and duration of B. monniera’s treatment is critical for bringing its optimal effects. For example, chronic administration of 300 mg oral B. monniera for about 5-12 weeks substantially improves the higher order of cognitive process in healthy humans. Such studies raise the value of herbal extracts over single molecular approaches.
Investigational herbal drugs
Herbal preparations of evolvulus alsinoides (shankhpushpi), withania somnnifera (ashwagandha), narbostachys jatamansi (jatamansi), celastrus paniculatus (malkangani), ginkobiloba, have been shown to enhance memory in humans. These are available in the market in various combinations such as “mentat capsule”, “more memory capsule”, “recall capsule”, “brahmi bati”, “shankhapushpi syrup” etc. Herbal preparation (such as mentat) containing brahmi, vach, ashwagandha, guduchi, shankhpushpi Jatamansi, tagar and triphala have been shown to enhance the memory. The combination of extract of brahmi, jatamansi and shankhpushpi shows the potent antidepressant action in mice. Indian hypericum perforatum has been significantly attenuated the electroconvulsive shock (ECS) induced deficit in retention of active and passive avoidance behavior of rats. Withania somnifera is also known to improve retention of a passive avoidance task and reverses the scopolamine induced disruption of acquisition and retention, attenuated acute electroconvulsive shock (ESC)-induced amnesia, and improves memory consolidation in mice receiving chronic ECS in mice. Amaran-thus paniculatus also improves learning ability of stressed mice, induced by radiation, in Hebb William’s Maze model. Celastrus paniculatus has also been known to decrease the turnover of nor-epinephrine, dopamine and serotonine in brain, and improve the learning and memory in rats. Aqueous extract of Celastrus paniculatus seed has been shown to have cognitive-enhancing properties in various experimental tasks (such as shuttle-box, step-through, step-down paradigm) in mice because of its antioxidant effect. Moreover, its seed oil reverses scopolamine-induced deficits in navigational memory performance. It has been shown to decrease the turnover of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) and known to be implicated in the involvement of learning and memory process. Aqueous extract of Centella asiatica (CA), used as an adjuvant with antiepileptic drugs, has the advantage of preventing cognitive impairment. Asiatic acid, a triterpene of CA, has been patented as a treatment for dementia and an enhancer of cognition by the Hoechst Aktiengesellschaft. The derivatives of asiatic acid is known to exert significant neuroprotective effects on cultured cortical cells by their potentiation of the cellular oxidative defense mechanisms. Besides, alcoholic extract of the roots of narbostachys jatamansi have also been shown to cause an overall increase in the levels of central monoamines and inhibitory amino acids.
Although various types of nootropic agents, available in the market, claim to enhance the memory, but their clinical and therapeutic efficiency is still controversial. The drug, which is effective in one clinical condition, may not give better therapeutic effect in other clinical condition. There is need to study the mechanism and pharmacology of these drugs and initiate clinical trials for potential candidates.
Competing interests - None
Received Date : 29 May 2009
Revised Date : 24 June 2009
Accepted Date : 11 July 2009
References
1. Tripathi A, Srivastava UC. Acetylcholinesterase :A Versatile Enzyme of Nervous System. Annals of Νeuroseieηces 2008;15(4):106-111.
2. Singh M, Mishra A. Prenatal topiramate exposure induced developmental changes in rat brain. Annals of Neurosciences 2005;12(2)16-18.
3. Prabhakar S, Saraf MK, Pandhi P, etal. Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice. Psychopharmacology (Berl)2008;200(1):27-37.
4. Anand A, Saraf MK, Prabhakar S. Sustained inhibition of brotizolam induced anterograde amnesia by norharmane and retrograde amnesia by L-glutamic acid in mice. Behav Brain Res 2007;182(1):12-20.
5. Saraf MK, Prabhakar S, Pandhi P, etal. Bacopa monniera ameliorates amnesic effects of diazepam qualifying behavioral-molecular partitioning. Neuroscience 2008;155(2):476-84.
6. Prabhakar S, Saraf MK, Pandhi P, etal. Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice. Psychopharmacology (Berl)2008.
(c) Annals of Neurosciences.All Rights Reserved