levetiracetam and Memory-Disorders

Topics: Amnesia; Anticonvulsants; Epilepsy; Humans; Levetiracetam; Male; Memory Disorders; Middle Aged

Imbalance in neural excitation and inhibition is associated with behavioral dysfunction in individuals with schizophrenia and at risk for this illness. We examined whether targeting increased neural activity with the antiepileptic agent, levetiracetam, would benefit memory performance in a preclinical model of schizophrenia that has been shown to exhibit hyperactivity in the hippocampus. Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Treatment with levetiracetam dose-dependently improved memory performance of the ketamine-exposed rats. In contrast, the antipsychotic medication risperidone was not effective in this assessment. Levetiracetam remained effective when administered concurrently with risperidone, supporting potential viability of adjunctive therapy with levetiracetam to treat cognitive deficits in schizophrenia patients under concurrent antipsychotic therapy. In addition to its pro-cognitive effect, levetiracetam was also effective in attenuating amphetamine-induced augmentation of locomotor activity, compatible with the need for therapeutic treatment of positive symptoms in schizophrenia.

Topics: Amphetamine; Animals; Central Nervous System Stimulants; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Levetiracetam; Locomotion; Male; Maze Learning; Memory Disorders; Nootropic Agents; Piracetam; Rats; Rats, Long-Evans; Schizophrenia

Dysfunction in topographical memory is a core feature of several neurological disorders. There is a large unmet medical need to address learning and memory deficits as a whole in central nervous system disease. There are considerable efforts to identify pro-cognitive compounds but current methods are either lengthy or labour intensive. Our test used a two chamber apparatus and is based on the preference of rodents to explore novel environments. It was used firstly to assess topographical memory in mice at different retention intervals (RI) and secondly to investigate the effect of three drugs reported to be beneficial for cognitive decline associated with Alzheimer's disease, namely: donepezil, memantine and levetiracetam. Animals show good memory performance at all RIs tested under four hours. At the four-hour RI, animals show a significantly poorer memory performance which can be rescued using donepezil, memantine and levetiracetam. Using this test we established and validated a spatial recognition paradigm to address topographical memory in mice by showing a decremental time-induced forgetting response and reversing this decrease in performance using pharmacological tools. The spatial recognition test differs from more commonly used visuospatial laboratory tests in both throughput capability and potentially neuroanatomical substrate. This test has the potential to be used to assess cognitive performance in transgenic animals, disease models and to screen putative cognitive enhancers or depressors.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Donepezil; Indans; Levetiracetam; Male; Maze Learning; Memantine; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Piperidines; Piracetam; Recognition, Psychology

Elevated excitability in the hippocampus has emerged as a key contributor to reduced memory function in aging and in cognitive impairment prodromal to Alzheimer's disease. Here, we investigated the relationship between neural activity and memory in the hippocampus and a connectional cortical network using an aged rat model of individual differences for memory impairment. The expression of cFos was used as a measure of pharmacologically induced neural activity. Aged memory-impaired rats exhibited elevated cFos relative to young adult and aged unimpaired rats in the CA3 subfield of the hippocampus and in several cortical regions including the retrosplenial, parietal, and orbitofrontal cortices. Strong correlations between cFos intensity and task performance across the activated network showed a tight coupling between excitability and cognitive phenotype in aging. Elevated neural excitability extending beyond the hippocampus to interconnected posterior cortex (retrosplenial/parietal) was reduced by treatment with levetiracetam, a therapeutic with behavioral efficacy that has previously translated from rodent models of age-related impairment and Alzheimer's disease to humans with amnestic mild cognitive impairment.

Topics: Animals; CA3 Region, Hippocampal; Cerebral Cortex; Cognition; Disease Models, Animal; Levetiracetam; Male; Memory; Memory Disorders; Piracetam; Proto-Oncogene Proteins c-fos; Rats, Long-Evans

Emerging evidence suggests that elevated hippocampal activation may be important for disrupting cognitive functions in aged subjects as well as patients with Alzheimer's disease (AD). Therefore, reducing deleterious overactivity of the hippocampus may have therapeutic benefits. This study was designed to compare the effects of levetiracetam, an antiepileptic drug, on memory deficits associated with normal aging and AD in mouse models. Pretraining administration of levetiracetam ameliorated memory impairments of aged C57BL/6 mice (17-20months of age) in the contextual fear conditioning paradigm. Acute levetiracetam immediately after training was also efficacious in rescuing contextual memory decline in aged mice, whereas administration at a later posttraining interval (3h) had no effect. These results suggest that suppressing overexcitation with acute levetiracetam around the time of acquisition or early consolidation may be sufficient to reverse memory decline associated with aging. In contrast, pretraining administration of levetiracetam was not able to rescue memory deficits in 5XFAD transgenic mice harboring amyloid plaque pathologies at moderate (6-8months old) or massive (12-15months old) levels, differentiating between normal aging- and AD-related memory impairments in the responsiveness to acute levetiracetam treatment.

Topics: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Conditioning, Operant; Disease Models, Animal; Fear; Female; Levetiracetam; Male; Memory; Memory Disorders; Mice; Mice, Transgenic; Nootropic Agents; Piracetam

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment.

Topics: Aging; Animals; Antigens, Nuclear; Behavior, Animal; CA3 Region, Hippocampal; Cell Count; Cognition; Glutamate Decarboxylase; Hippocampus; Imaging, Three-Dimensional; Immunohistochemistry; Interneurons; Levetiracetam; Male; Memory Disorders; Nerve Tissue Proteins; Neuropeptide Y; Nootropic Agents; Perfusion; Piracetam; Rats; Rats, Long-Evans; Somatostatin

Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of older and newer AEDs on cognitive performance in postoperative HGG patients.. We selected HGG patients from 3 separate cohorts for use of older, newer, or no AEDs, as they represented distinct treatment eras and provided the opportunity to compare older and newer AEDs. In all 3 cohorts, patients were included within 6 weeks following neurosurgery before the start of postoperative treatment. Cognitive functioning was evaluated by an extensive neuropsychological assessment, executed in 6 cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed).. One hundred seventeen patients met the inclusion criteria; 44 patients used no AED, 35 were on monotherapy with a newer AED (all levetiracetam), and 38 were on monotherapy with an older AED (valproic acid or phenytoin). Patients on older and newer AEDs performed equally well as patients not on an AED, and patients on levetiracetam performed even better on verbal memory tests than patients not on an AED. Post-hoc analyses revealed that within the group using older AEDs, patients on valproic acid performed better than patients on phenytoin.. Neither levetiracetam nor valproic acid was associated with additional cognitive deficits in HGG patients. Both AEDs even appeared to have a beneficial effect on verbal memory in these patients.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Brain Neoplasms; Cognition Disorders; Female; Glioma; Humans; Levetiracetam; Male; Memory Disorders; Middle Aged; Neoplasm Grading; Neuropsychological Tests; Piracetam; Prognosis; Prospective Studies; Psychomotor Performance; Quality of Life; Verbal Learning; Young Adult

A recent study by Bakker et al. shows that a low dose of the antiepileptic drug levetiracetam reduces hippocampal hyperactivity in elderly humans with amnestic mild cognitive impairment and improves hippocampal memory function. This points towards a new treatment strategy for age-related memory impairment by reducing deleterious overactivity of the hippocampus.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Cognitive Dysfunction; Hippocampus; Humans; Levetiracetam; Memory; Memory Disorders; Piracetam

Status epilepticus (SE) is often followed by severe cognitive impairment, including memory impairment. Previous studies have shown that SE is associated with impairment of single cells in the hippocampus that fire action potentials when the animal is in a specific location in space, the so-called place cells, and that place cell function correlates well with performance in tasks of visual-spatial memory. Place cell patterns therefore appear to be an excellent measure of spatial memory and may serve as a tool to assess seizure-induced impairment in memory. In this study we determined the relationship between visual-spatial memory and place cell function following SE. In addition, we determined if levetiracetam (LEV), an antiepileptic drug with a novel mechanism of action, can improve cognitive function and place cell firing patterns when administered following SE. SE was induced in adult male rats which were then randomized to post-SE treatment with LEV or normal saline (NS) treatment for 14 days. Non-SE control rats also were randomized to LEV or NS. Following discontinuation of LEV rats were tested for visual-spatial memory in the Morris water-maze and then underwent unit recording in the CA1 region of the hippocampus. Brains were then evaluated for cell loss and mossy fiber sprouting. SE was associated with severely impaired performance in the water-maze with SE rats demonstrating no learning over four days of testing. Paralleling this memory deficit was a marked disturbance in firing patterns of pyramidal neurons in CA1. Non-SE rats learned quickly over four days of water-maze testing and had normal pyramidal cell firing patterns. LEV had no major effects on water-maze performance or place cell function. Histopathological examination of the brains showed severe cell loss in CA1 in all of the SE rats with lesser degrees of injury in CA3 and the hilus. LEV treatment resulted in less histological damage in the hippocampus but had no effect on visual-spatial function or place cell physiology in either control or SE rats.

Topics: Animals; Anticonvulsants; Behavior, Animal; Cell Death; Disease Models, Animal; Electroencephalography; Hippocampus; Levetiracetam; Male; Maze Learning; Memory Disorders; Pilocarpine; Piracetam; Random Allocation; Rats; Rats, Sprague-Dawley; Status Epilepticus; Swimming; Water