Melatonin and Ischemic Stroke: Mechanistic Roles and Action

Figure 1

The flowchart shows a complex webbed array of events involved in the pathogenesis of cerebral ischemic injury and the role played by melatonin as neuroprotectant. Stroke onset triggers a chain of mechanisms, including activation of glutamate receptors, calcium overload with subsequent activation of apoptosis, and toxic radical release. Induction of mitochondrial permeability transition by opening of the permeability transition pore (mPTP) dissipates the mitochondrial membrane potential. These events result in cessation of electron transport and ATP formation, mitochondrial swelling, and permeabilization of the outer mitochondrial membrane, allowing the efflux of several proapoptotic molecules, including cytochrome and apoptosis-inducing factor (AIF). In turn, cytochrome and AIF activate a series of downstream effectors that eventually lead to the fragmentation of nuclear DNA resulting in cellular death. The cell may be also destructed by apoptosis or necrosis in case of mPTP opening and PARP activation. Triggers such as inflammation initiate the “extrinsic” pathway to programmed cell death. Conversely, calcium overload and oxygen free radicals appear to exert their effect predominantly at the mitochondrial level via the “intrinsic” pathway. In addition, crossover activation between the “extrinsic” and “intrinsic” pathway may take place through proapoptotic intermediates such as the BID protein. AIF, ATP, adenosine triphosphate; BAK; BAX, Bcl₂-associated × protein; Bcl₂, B-cell lymphoma 2 protein family; Bcl-X_L, B-cell lymphoma-extra-large; and BID, p53 tumor suppressor protein. The ischemia-induced inflammation then further maintains these processes via cytokine release and iNOS activation leading to oxidative stress and necrosis. Melatonin limits the extent of ischemic brain injury by interacting at multisteps of the ischemic cascade. The cross indicates the interference by melatonin.