Memantine and Recovery After Stroke

July 3, 2014
Alisa G. Woods, PhD

The Alzheimer drug may help repair some damage caused by stroke. In a rodent model, treated animals showed improved motor behavior and restored sensory mapping in the cortex. Here, more about the proposed mechanism.

A recent mouse study1 has indicated that memantine, an Alzheimer disease medication, could aid in recovery from the damage caused by stroke. Motor behavior improved in memantine-treated animals, and sensory mapping seemed to reestablish in the cerebral cortex. The effects could be a result of direct stimulation of brain-derived neurotrophic factor (BDNF) and its receptor.

Stroke is the fourth leading cause of death throughout the world and a major contributor to medical complications.2 A stroke responds best to immediate treatment, and positive outcomes are limited by the small window of opportunity when brain damage occurs after the brain has been deprived of blood.  Interventions include clot-busting drugs and anticoagulants that must be given within a few hours after the stroke occurs. Unfortunately, researchers have not yet developed medications to directly protect against brain damage, despite many years of work and experimental evidence that brain recovery from stroke is possible.

Memantine is an oral medication approved for the treatment of mild to moderate Alzheimer disease. While all other approved Alzheimer drugs act to increase levels of acetylcholine by blocking the enzyme acetylcholinesterase, memantine acts differently. Memantine blocks the neurotransmitter glutamate, specifically at the N-methyl-D-aspartate (NMDA) glutamate receptor. This difference might offer clues to its possible effectiveness in stroke recovery.3

Glutamate is the most abundant neurotransmitter in the brain. It is found in 50% of all neural tissue and is critical for neural excitation. Over-abundance and hyperactivity of glutamate contributes to neurotoxicity-overstimulation by glutamate causes cell death. The energy deficiency caused by stroke can trigger excessive glutamate release and excitotoxicity. For this reason, a glutamate antagonist could be an effective treatment for stroke.

The study was reported in the June 17 issue of the journal Stroke. The scientists gave mice memantine at 30 mg/kg per day in drinking water starting 2 hours after a photothrombotic stroke. A control group was given a 2% sucrose vehicle in drinking water after the induced stroke. This stroke animal model uses photo-activation of previously injected light-sensitive dye. With light exposure, the dye is activated and produces oxidative damage of blood vessels in the brain

The researchers found no difference between groups in the size of infarcts that resulted from the induced stroke. However, they did observe improvements in motor ability, as measured by grid walking, when the memantine-treated animals were compared to controls.  At 28 days following the stroke, brain imaging showed in the treated animals a significant increase in activation area in sensory maps that corresponded to forepaw movement. In addition, treated animals had less astrogliosis-a measure of brain scarring-and more vasculature around the infarcted area of cerebral cortex than control animals.

Western blot analysis (protein immunoblot) revealed that the positive changes induced by memantine could be associated with activation by the drug of BDNF and phosphorylated-tropomyosin-related kinase-B (trkB) receptor expression. BDNF is a “neurotrophin” growth factor that acts as a survival and also as a neuronal differentiation factor. BDNF acts on trkB receptors to exert its effects. Interestingly, this means that the effects of memantine could be the result of direct stimulation of trophic factor and neuroplasticity, rather than of (or perhaps in addition to) its direct glutamate-blocking activity.

The authors concluded “Our results suggest that memantine improves stroke outcomes in an apparently non-neuroprotective manner involving increased brain-derived neurotrophic factor signaling, reduced reactive astrogliosis, and improved vascularization, associated with improved recovery of sensory and motor cortical function. The clinical availability and tolerability of memantine make it an attractive candidate for clinical translation.”

References:

1. López-Valdés HE, Clarkson AN, Tayn A et al., Memantine enhances recovery from stroke. Stroke. 2014; pii: STROKEAHA.113.004476.

2. Kinlay S. Changes in stroke epidemiology, prevention, and treatment. Circulation.  2011;124:e494–e496.

3. Peng D, Yuan X, Zhu R. Memantine hydrochloride in the treatment of dementia subtypes. J Clin Neurosci. 2013;20:1482-1485.

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