Indian J Physiol Phannacol 1994; 38(4) : 241-251 RE\llEW ARTICLE DRUGS INFLUENCING COGNITIVE FUNCTION ALICE KURUYILLA* AND YASUNDARA DEYI Department ofPharmacology. Christian Medical College. Vellore - 632 002 DRUGS INFLUENCING COGNITIVE FUNCTION cerebrovascular disorders with dementias and reversible dementias. Drugs can inOuence cognitive function in several different ways. The cognitrve enhancers or nootropics Primary degenerative disorders include the have become a major issue in drug development during subgroups senile dementia of the Alzheimer's type the last decade. Nootropics arc defined as drugs that (SDAT), Alzheimer's disease, Picks disease and generally increase neuron metabolic activity, improve Huntington's chorea (4). Alzheimer's disease usually cognitive and ,'igilance level and are said to have occurs in individuals past 70 years old and appears to antidemcntia effect (I). These drugs are essential for be in part genetically determin'd (5). the treatment of geriatric disorders like Alzheimer's which have become one of the major problems socially Pathophysiology oj Alzheimer's disease : and medically. Considerable evidence has been gathered Extensive research in the recent years has made major in the last decade to support the observation that advances in understanding the pathogenesis of children with epilepsy have morc learning difficulties Alzheimer's disease (6). The hallmark lesions of than age matched controls (2, 3). Anti-epileptic drugs Alzheimer's disease are neuritic plaques and are useful in controlling the frequency and duration of neurofibrillary tangles. Two amyloid proteins seizures. These drugs can also be the source of side accumulate in Alzheimer's disease, these arc beta effects including cognitive impairment. Since ]975, amyloid protein and paired helical filament protein (7). greater attention has been given to assess the cognitive Based on the amyloidoses associated with other effects of anti-epileptic drugs. By learning more about diseases, three mechanisms for amyloid formation cognitive effects of anti-epileptic drugs, patients can have emerged. One mechanism involves posllransitional be offered optimal therapy combining excellent seizure event which render a normal protein amyloidogenic. control with the least possible negative impact on Proteolysis, phosphorylation, glycosyiation and intellectual functioning. This review is an update on transglutamination may be the relevant, informatiOn on drugs which can improve cognitive posttranslational events in Alzheimer's disease, another function as well as those which may produce cognitive mechanism for amyloid formation results from dysfuction. expressiol1 of an abnormal gene which in the case of familial Alzheimer's disease may be an rmportant Diseases associated with cognitive impairment: etiological component. A third mechanism involves the Dementia is characterised by decline in memory, accumulatiol1 of a normal protein to a threshold thinking and emotional functions. In the descriptive concentration that spontaneously forms amyloid. diagnosis of dementia disorders, different aspects arc These mechanisms of amyloid formation can becom mentioned; benign senile forgetfulness, primary targets for drug therapy. The number of neuritic plaques degenerative disorders, secondary dementias, and neurofibrillary tangles arc positively correlated to *CorrcsponJing AUlhor 242 Kuruvilla and Devi Indian J Physiot Pharmacol 1994; 38(4) the severity of clinical symptoms and cognitive studied in rats and mice by various workers. Passive impairment. avoidance with punishment reinforcement termed as step-through method, and two-way active avoidance Neurochemical and neuroendocrine disturbances with punishment reinforcement known as 'shuule-box' of Alzheimer's and SDAT have been described by are reponed as useful methods of testing for learning various workers. Olney reported that there is deficiency and memory. in these animals (15). Various test drugs of the neurotransmitter acetylcholine (8). Autopsy have been used in experimental studies to observe their studies have suggested that cholinergic neurons are effects on learning and memory. These include selectively lost in these disorders. Cerebrospinal fluid nootropics such as j1iracetam, fipexide, oxiracetam, concentration of acety.lcholine showed good correlation adafenoxate, meclofenoxate, citicholine, aniracetam, with the degree of cognitive impairment (r = 0.7) in a standardised ginseng extract, cholinomimetic sample of carefully diagnosed patients; but metabolites compounds like scopolamine, linopirdine, of other neurotransmitters were not related to cognitive cholinesterase inhibitors such as taerine, amiridin, state. This suggest that CSF Ach may be a valid physostigmine and drugs inOuencing monoaminergic measure of cholinergic; degeneration (9). Reduction of neurotransmitter such as MAO inhibitors and 5-HT choline acetyltransferase activity, a cholinergic marker uptake blockers. has been significantly correlated to the severity of dementia (10). Agnoli et al (11) also observed a Age related changes on learning ana memory correlation among the degree of memory loss, has been observed by Burov et al (16). 18 months old intellectual impairment, the quantity of senile plaques, rats showed much less learning abiliLy in comparison and a decrease in choline acetyltransferase and wiLh that of 3 months old rats. 20 days treatment of acetylcholinesterase activity in patients affected by old rats with amiridin. lacrine and piraceLam improved senile dementia of the Alzheimer's type. latency in passive avoidance test to the level of 3 months old rats. Mondadori et al (17) also studied the The monoaminergic neurotransmission deficit effects of new compound on age-related cognitive seen in dementia of the Alzheimer's type (DAT) is dysfunctions in rats using one way active avoidance linked to a known increased activity of type B cerebral situation. Petkov et al (18) used rats of age varying monoamine oxidase (12). Drugs that can b'lock this from 2 to 22 months in experiments using active abnormal activity have been found to be useful in the avoidance with punishment reinforcement (maze and treatment of some cognitive delicits. Postmortem human shuttle-box and passive avoidance (step-down) to brain studies have shown a disturbed metabolism of observe age related differences in memory. On their serotonin and overactivity of neuroendocrine controlling factors in the hypothalamus (13). Somatostatin is study the nootropics adafenoxate, meclofenoxate, consistently diminished in brains of patients with citicholine, aniracetam and the standardised ginseng Alzheimer's disease (14). Cortisol dysregulation may extract administered orally for 7-lO days usuaUy be a marker for abnormalities in other neurotransmitter facilitated learning and improved memory in the nUs systems, particularly the noradrenergic system. of all ages. Old rats showed pronounced favourable Aetiological factors associated with Alzheimer's disease effects by some of the indices. The biochemical changes arc genetic factors, aluminium or other toxic factors, observed with aging are d.ecrease in the activity of immunological disturbances, disturbed glucose acetylcholinesterase, reduction of unsaturated fatty metabolism, deficiency of essential nutrients and stress. acids, the increase of cholesterol content and the increase of microviscosily of membranes of brain A1\L\IALS l\IODELS FOR LABORATORY EVALUATION synaptosomes. Mult,iple treatment with amiridin, OF COG1\ITIVE FCNCTION piracetam and tacrine normalised these indices. A. Learning and memory Scopolamine impaire i TTJcmory has been used The changes in learning and memory has been, by Petkov et al (19) to detemlme drug effects. In these Indian J Physiol Phannacol 1994; 38(4) Drugs Influencing Cognitive Function 243 experiments scopolamine (2 mg/kg, ip) was used and clonidine has been used by Lazarova, Bakarova and step-through passive avoidance method was used to co-workers (23) to observe the inOucnce of nootropics determine the memory changes. Test drugs were given Uke piracetam, aniracetam, mcclofenoxate and fipcxide. for 7 days before training or immediately after training. The changes ·in learning and memory were studied by The test drugs adafenoxate, meclofenoxate, piracetam two way active avoidance with punishment and citicholine prevented the scopolamine induced reinforcement (shuttle-box). Clonicline injected retrograde amnesia partially or completely. Lenegre et intraperitoneally at a dose of 0.1 mg/kg immediately al (20) used scopolamine, diazepam and after a one-day shuttle box training significantly electroconvulsive shock to produce amnesia in mice impaired retention. A 5-day treatment before the with passive avoidance procedure. Amnesia was training session with test drugs completely abolished induced by injecting scopolamine or diazepam (l mg/ the memory-impairing effect of clonidine. Sharma and kg, ip), 30 min before the passive avoidance task. Kulkarni (24) have used elevated plus-maze as the Electroconvulsive shock is applied immediately after method to evaluate learning and memory mechanisms the first session of the passive avoidance task for in rats and mice. Transfer-latency (TL) was used as a producing amnesia. Pintcetam when administered in parameter for acquisition and retention of memory varying doses 60 min before first session attenuated process on elevated plus-maze in rats and mice. the memory deficits induced by the three amnesic Shorwned TL on 2nd day trial in old