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.