Involvement of nitric oxide in learning & memory processes.

Nitric oxide (NO), synthesized from the amino acid, L-arginine by nitric oxide synthase (NOS) has received attention as a neurotransmitter in the brain. NO has been found to induce cognitive behaviour in experimental animals. In order to show evidence for the involvement of NO in learning and memory processes, the reports indicating the effects of its precursor, donors, and inhibitors of its synthesis in mammals, birds, fishes and invertebrates have been reviewed. Further, learning and memory impairment occurring in man and animals due to defective NO activity in the brain due to pathological conditions such as epilepsy, stress, diabetes and side effects of therapeutic agents and reversal of this condition by L-arginine and NO donors have been included. In addition, the reports that indicate ageing-induced impairment of cognition that is known to occur in Alzheimer's disease due to deposition of the toxic protein, beta amyloid and the effect of L-arginine and NO donors in preventing dementia in these patients have been reviewed.

A reversal by L-arginine and sodium nitroprusside of ageing-induced memory impairment in rats by increasing nitric oxide concentration in the hippocampus.

In the present study, memory formation to an acquired pole-climbing shock avoidance task was tested in young adult (3-4 month-old) and aged (24-25 month-old) rats. The data were correlated with the activity of nitric oxide synthase (NOS) and the concentration of nitric oxide (NO) in the hippocampus, midbrain, cortex and cerebellum. Motor co-ordination was tested in both groups. Memory test and NO determination were carried out in another set of young and aged groups, 15 min after intraperitoneal administration of NO precursor, L-arginine (500, 1000 mg/kg) or NO donor, sodium nitroprusside (SNP) (1.25, 2.5 mg/kg). No difference was found between the motor co-ordination performances of young and aged animals. But the aged animals were not able to perform the shock avoidance pole-climbing task as readily as the young animals. It is suggestive of an impairment of memory formation of the acquired task in the aged animals. The synthesis of NO which is known to regulate memory process in the hippocampus, was lower in this brain region of aged animals as compared to that in young animals. L-arginine (1000 mg/kg) and SNP (2.5 mg/kg) increased the concentration of NO in the hippocampus and shortened the time of pole-climbing shock avoidance task in young as well as in aged animals. These results lead to a conclusion that a decreased synthesis of NO in the hippocampus in responsible for an impairment of memory formation in aged animals and that an increase in the concentration of NO in the hippocampus by L-arginine (1000 mg/kg) or SNP (2.5 mg/kg) results in a promotion of memory formation in the young adult rats and a reversal of memory deterioration in the aged animals. Thus, NO precursor and NO donor may be effective in reverting cognitive dysfunction associated with Alzheimer's disease, an ageing-induced neurodegenerative disease.

The effect of L-arginine on the memory impairing action of phenobarbitone in rats that convulsed after the injection of picrotoxin.

Nitric oxide (NO) has been demonstrated to enhance memory formation in experimental animals. However, the effect of NO precursor, L-arginine has never been tested on the memory impairing action of the aniepileptic drug, phenobarbitone independently and concurrently with the convulsant, picrotoxin (PCT). In view of this, in the present study, rats that acquired the shock avoidance task were treated with PCT (5 mg/ kg). Twenty four h later these animals were injected with L-arginine (500, 1000 mg/kg) and phenobarbitone (10, 20 mg/kg). Retention of the acquired task was tested 30 min later. The effect of these compounds were correlated with the changes produced by them on the concentration of NO in the brain. PCT and phenobarbitone (20 mg/kg) inhibited memory process independently and concurrently. NO concentration was not altered by phenobarbitone but was decreased in PCT-treated animals. L-arginine (1000 mg/kg) increased the concentration of NO in PCT and phenobarbitone treated animals and prevented these compounds from impairing memory process independently and concurrently. These results lead to a conclusion that L-arginine may be used in combination with phenobarbitone to prevent both the cognitive side effect of the antiepileptic drug and the impairment of memory that is associated with the convulsion disorder.

Effect of 7-nitroindazole alone and in combination with phenobarbitone and diazepam on picrotoxin-induced convulsions in rats.

There are no reports on the effect of 7-nitroindazole (7-NI) on chemically-induced convulsions. Hence, in the present study, its (100 and 200 mg/kg) action was tested alone and in combination with phenobarbitone (20 mg/kg) and diazepam (0.25 mg/kg) on picrotoxin (PCT)-induced convulsions in rats. The changes produced by 7-NI on nitric oxide synthase (NOS) activity and nitric oxide (NO) concentration were determined in the brain. The effect of 7-NI was tested in L-arginine (1000 mg/kg) pretreated (30 min) animals. The smaller dose (100 mg/kg) of 7-NI did not alter NOS activity and NO concentration, but inhibited PCT-induced convulsions indicating that its anticonvulsant action was devoid of an involvement of NO. But, an inhibition of NOS activity, by a larger (200 mg/kg) dose of it, resulted in a promotion of the convulsant action of PCT and in an impairment of the anticonvulsant effect of both phenobarbitone and diazepam. The proconvulsant action of 7-NI was reverted by L-arginine. These results suggest that 100 and 200 mg/kg of 7-NI produce distinguishable action on PCT-induced convulsions because NOS activity is inhibited by 200 mg/kg and not by 100 mg/kg of it. The results further suggest that NO acts as anticonvulsant and that the NOS inhibitors, like 7-NI, cannot be used as an anticonvulsant either alone or in combination with other anticonvulsants.