Cerebral ischemia is a result of reduced blood flow to tissues. The consequence is a rapid depletion of energy stores and the subsequent triggering of a complex cascade of cellular events including membrane depolarization, calcium influx, excessive production of free radicals, and the activation of necrotic as well as apoptotic pathways. The above reactions further perpetuate initial ischemic neuronal damage. Cytokines such as tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase are involved in post-ischemic inflammatory responses that further exacerbate ischemic brain damage. Neuroprotective effects of nicotinamide (NAm), an amide form of vitamin B3, have been well-documented in other earlier studies. NAm can significantly reduce brain infarctions and improve neurologic outcome following ischemic stroke in various strains of both male and female rats. The protective effect of NAm is largely dose-specific at 500 mg/kg. However, a higher dose (750 mg/kg) is required in hypertensive rats. NAm also prevents energy depletion by facilitating neuronal adenosine triphosphate (ATP) production during cerebral ischemia. It also blocks cellular inflammatory response and has the ability to inhibit early apoptotic phosphatidylserine exposure and late nuclear DNA degradation induced by an experimental stroke as demonstrated in some studies. Accordingly, NAm exhibits multifaceted neuroprotective effects and can prevent neuronal death by inhibiting post-ischemic ATP depletion, inflammation, and necrotic as well as apoptotic events.
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