The Indirect NMDAR Antagonist Acamprosate Induces Postischemic Neurologic Recovery Associated with Sustained Neuroprotection and Neuroregeneration

Abstract

Cerebral ischemia stimulates N-methyl-D-aspartate receptors (NMDARs) resulting in increased calcium concentration and excitotoxicity. Yet, deactivation of NMDAR failed in clinical studies due to poor preclinical study designs or toxicity of NMDAR antagonists. Acamprosate is an indirect NMDAR antagonist used for patients with chronic alcohol dependence. We herein analyzed the therapeutic potential of acamprosate on brain injury, neurologic recovery and their underlying mechanisms. Mice were exposed to cerebral ischemia, treated with intraperitoneal injections of acamprosate or saline (controls), and allowed to survive until 3 months. Acamprosate yielded sustained neuroprotection and increased neurologic recovery when given no later than 12 hours after stroke. The latter was associated with increased postischemic angioneurogenesis, albeit acamprosate did not stimulate angioneurogenesis itself. Rather, increased angioneurogenesis was due to inhibition of calpain-mediated pro-injurious signaling cascades. As such, acamprosate-mediated reduction of calpain activity resulted in decreased degradation of p35, increased abundance of the pro-survival factor STAT6, and reduced N-terminal-Jun-kinase activation. Inhibition of calpain was associated with enhanced stability of the blood-brain barrier, reduction of oxidative stress and cerebral leukocyte infiltration. Taken into account its excellent tolerability, its sustained effects on neurologic recovery, brain tissue survival, and neural remodeling, acamprosate is an intriguing candidate for adjuvant future stroke treatment.

2-Methyl-5H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine, an edaravone analog, exerts neuroprotective effects against acute ischemic injury via inhibiting oxidative stress

“…To test the BBB permeability, we infused the two drugs and Evans blue into tMCAO rats immediately and at 22 hours after reperfusion, respectively, and measured the Evans blue concentration in the contralateral and ipsilateral hemisphere at 24 hours after reperfusion. Consistent with the previous reports [ 28 ] , ischemia dramatically increased BBB permeability in the ipsilateral hemisphere, and more importantly, TR and edaravone rescued ischemia-induced BBB dysfunction ( Fig. 2H ).…”

Calcium Carbonate Attenuates Withdrawal and Reduces Craving: A Randomized Controlled Trial in Alcohol-Dependent Patients

“…An imbalance in calcium homoeostasis has been shown to be associated with neurological diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury [33]. When given no later than 12 h after a stroke, even acamprosate showed neuroprotective efficacy and increased neurological recovery in an animal model [34]. The onset of Alzheimer's disease is potentially associated with previous calcium-signaling dysregulation and even low calcium content in drinking water [35].…”

The Effects of N-Methyl-D-Aspartate Receptor Blockade on Oxidative Status in Heart During Conditioning Maneuvers

“…Several authors indicated the beneficial effects of NMDAR antagonists, primarily MK-801 and memantine, in various models of neuron damage including hypoxia-ischemia and harmful effects of oxygen and glucose deprivation (27,28). Doeppner et al showed that acamprosate, as indirect NMDAR antagonist, exhibited neuroprotective effects if administered 12 hours before stroke, through inhibition of calpain-mediated pro-injurious signaling cascades (29).…”