Modification of Hippocampal Markers of Synaptic Plasticity by Memantine in Animal Models of Acute and Repeated Restraint Stress: Implications for Memory and Behavior

Abstract

Stress is any condition that impairs the balance of the organism physiologically or psychologically. The response to stress involves several neurohormonal consequences. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and its release is increased by stress that predisposes to excitotoxicity in the brain. Memantine is an uncompetitive N-methyl D-aspartate glutamatergic receptors antagonist and has shown beneficial effect on cognitive function especially in Alzheimer's disease. The aim of the work was to investigate memantine effect on memory and behavior in animal models of acute and repeated restraint stress with the evaluation of serum markers of stress and the expression of hippocampal markers of synaptic plasticity. Forty-two male rats were divided into seven groups (six rats/group): control, acute restraint stress, acute restraint stress with Memantine, repeated restraint stress, repeated restraint stress with Memantine and Memantine groups (two subgroups as positive control). Spatial working memory and behavior were assessed by performance in Y-maze. We evaluated serum cortisol, tumor necrotic factor, interleukin-6 and hippocampal expression of brain-derived neurotrophic factor, synaptophysin and calcium-/calmodulin-dependent protein kinase II. Our results revealed that Memantine improved spatial working memory in repeated stress, decreased serum level of stress markers and modified the hippocampal synaptic plasticity markers in both patterns of stress exposure; in ARS, Memantine upregulated the expression of synaptophysin and brain-derived neurotrophic factor and downregulated the expression of calcium-/calmodulin-dependent protein kinase II, and in repeated restraint stress, it upregulated the expression of synaptophysin and downregulated calcium-/calmodulin-dependent protein kinase II expression.

Beneficial effects of environmental enrichment on behavior, stress reactivity and synaptophysin/BDNF expression in hippocampus following early life stress

“…The possibility that BDNF and SYN expression may have been affected by the acute stress (i.e., rotation) applied at the end of the experiments cannot be excluded. Previous studies have shown that acute stress alters the expression of neurotrophic factors and synaptic regulatory proteins and these alterations may be responsible for some of the morphological and behavioral changes observed after stress exposure (Amin et al, 2015; Gao et al, 2006; Smith et al, 1995; Thome et al, 2001). Specifically, acute stress induces a brain region‐dependent differential expression of BDNF (Lakshminarasimhan and Chattarji, 2012).…”

Memantine can relieve the neuronal impairment caused by neurotropic virus infection

“…Memantine is a noncompetitive antagonist (moderate affinity) of NMDA receptors; it can significantly alleviate the symptoms caused by NMDA receptor imbalance, and reduce the symptoms of neurological disorders and related disorders, such as Alzheimer's disease (AD), glaucoma, epilepsy, neurodegenerative diseases, cranial nerve injury, drug addiction, cerebral ischemia, depression, anxiety, agitation, and drug dependence …”

“…14 Memantine is a noncompetitive antagonist (moderate affinity) of NMDA receptors 15,16 ; it can significantly alleviate the symptoms caused by NMDA receptor imbalance, 17 and reduce the symptoms of neurological disorders and related disorders, such as Alzheimer's disease (AD), glaucoma, epilepsy, neurodegenerative diseases, cranial nerve injury, drug addiction, cerebral ischemia, depression, anxiety, agitation, and drug dependence. 18,19 Since memantine is able to penetrate the BBB, concentration of memantine in the cerebrospinal fluid is similar to that in the blood. Therefore, memantine is used to treat a variety of neurological diseases.…”

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

“…This mechanism of action may be relevant in schizophrenia as well. Galantamine [21] and memantine [22, 23] have increased brain-derived neurotrophic factor (BDNF). Finally, gal antamine [24-26] and memantine [27] have antioxidant activity.…”