Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats

Abstract

In the present study, Memantine (MN) an uncompetitive N-methyl-d-aspartate (NMDA) open channel blocker has been investigated for its suitable therapeutic time-window on the basis of its influence on behavioural and biochemical changes in rats subjected to transient focal ischemia. MN (20 mg/kg, ip) was administered at pre, during and post ischemic state and the extent of neuroprotection was compared to ascertain its therapeutic time-window in stroke treatment. Neuroprotective effect was assessed by measuring glutamate, glutamine synthetase, glutathione, Na⁺K⁺ATPase, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD), lactate and pyruvate levels. Middle cerebral artery occlusion produced neurological deficits, anxiogenic behaviour, histological changes, increased glutamate levels along with depletion of Na⁺K⁺ATPase, energy stores such as ATP, NAD, lactate, and antioxidant glutathione. MN significantly restored glutamate, glutamine synthetase, Na⁺K⁺ATPase and lactate levels on preischemic administration. In addition, MN reversed the altered neurological and behavioural paradigms significantly and prevented the neurodegeneration on preischemic treatment. However, it failed to exert any effect on energy metabolite (ATP and NAD) levels irrespective of the treatment phase. Based on the present data, it is summarized that the suitable therapeutic time window of MN is preischemic phase in stroke and it possesses only a subjective role in reversing ischemic brain biochemical alterations preferentially in favor of neuronal homeostasis.

Introduction

Cerebral ischemia, one of the leading causes of medical morbidity and mortality in geriatric population often results in irreversible brain damage. Focal impairment of cerebral blood flow restricts the delivery of substrates, particularly oxygen and glucose. The biochemical alterations following cerebral ischemia starts with depletion of energy phosphates and disruption of ion homeostasis with a consequent increase in the extracellular potassium and glutamate levels rendering over activation of N-methyl-d-aspartate receptors (NMDARs), intracellular Ca²⁺ over load and finally cell death (Arundine and Tymianski, 2004) as time progresses. It will be more appropriate if the therapeutic interventions are based on the bio- and neurochemical status following ischemic-reperfusion (IR).

Various therapeutic strategies are employed in the treatment of stroke, with NMDA blockers gaining greater interest in the recent past. NMDAR antagonists have often failed as therapeutic agents because of their debilitating side effects (Lipton, 2004). Memantine (1-amino-3,5-dimethyladamantane), an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist reduces glutamatergic excitotoxicity. Memantine (MN) has been approved in Europe in 2002 and United States in October 2003 for treatment of moderate to severe Alzheimer's disease. Unlike other NMDA receptor antagonists, memantine possesses fast on/off kinetics, low-moderate affinity and it also blocks the effects of excessive glutamate while preserving the physiologic activation of NMDA receptors (Johnson and Kotermanski, 2006).

Earlier results were paradoxical with NMDA agents administered at different time points of IR (Macleod et al., 2004, Ikonomidou and Turski, 2002). In some failed stroke clinical trials, treatments were administered outside the temporal window of efficacy (Labiche and Grotta, 2004) of the drugs. Hence, a study evaluating the correlation of the efficacy of the drugs with different time episodes of ischemia might yield a meaningful result in the treatment of stroke. The present study demonstrates the suitable therapeutic time window of MN and its role on behavioural and biochemical alterations in rats subjected to middle cerebral artery occlusion (MCAO).