Ischemic stroke is a cerebrovascular health condition that is caused by blockage in an artery that supply blood to the brain. The blockage reduces blood flow and oxygen supply to the brain, leading to damage or death of the brain cells. If blood circulation is no restored quickly, brain damage can be permanent.
Ischemic stroke contribute to about 80% of all strokes and is the second leading cause of human death and third leading cause of disabilities. Thus, ischemic stroke is a threat to human health and a huge burden to the health care systems.
Pathophysiology of ischemic stroke
Ischemic occlusion generates thrombotic and embolic conditions in the brain. In thrombosis, blood flow is affected by narrowing of vessels due to atherosclerosis. Eventually, the built-up plague will constrict the vascular chamber and form clots, causing thrombotic stroke. However, in embolic stroke, the blood flow to the brain reduces, causing severe stress and untimely cell death (necrosis).
Necrosis is followed by disruption of the plasma membrane, organelle swelling and leaking of the cellular contents into extracellular space and loss of neuronal unction.
Excitotoxicity is the process in which excess quantities of the excitatory neurotransmitter, glutamate, over-activates N-methyl-D-aspartic acid (NMDA) receptors and induces neuronal death.
Restricted cerebral blood flow in the ischemic stroke depletes oxygen and nutrient supply, which are required by neurons to maintain ionic homeostasis. This disruption of ionic gradients depolarizes the cell and triggers the release of excitatory neurotransmitters, glutamate, into the synaptic space.
Energy depletion impairs the function of re-uptake transporters, so they are unable to clear excess glutamate. This results in the accumulation of glutamate in the extracellular space and the consequent over-activation of glutamate receptors of post-synaptic neurons.
Molecular mechanism of glutamate in Excitotoxicity
The excitatory effects of glutamate are exerted through the activation of three major types of ionotropic receptors and several classes of metabotropic receptors linked to G-proteins. The major ionotropic receptors activated by glutamate are commonly referred to as N-methyl-D-aspartic acid, -Amino-3-hydroxyl-5-mehylisoxole-4-propionate (AMPA) and kainic acid (KA) receptors. These ionotropic receptors are ligament-gated ion channels permeable to various cations.
In neurodegenerative diseases, metabotropic (mGluR) receptors mediate slow synaptic responses, owing to their coupling with intracellular G-proteins. The mGluR1 and mGluR2 subunit-subtypes, for example, which exist in a number of spliced forms, are coupled to the inositol trisphosphate (IP3)/ Ca2+ signal transduction pathway and can thus affect protein kinase activation and stimulation of Ca2+ release from neuronal stores, both of which can trigger delay in cell death process.
Dual roles of NMDA receptors in neuronal survival and death
The dual roles of NMDA receptors in in neuronal survival and death depend on the subcellular locations and subtypes of the receptors that are activated. Stimulation of synaptic NMDA receptors activates pro-survival signaling pathways; whereas the activation of extrasynaptic NMDA receptors is associated with pro-death pathways. Synaptic NMDA receptors stimulation activates the phosphoinositide-3-kinase (PI3)/Akt kinase pathway, cAMP-response element binding protein (CREB)-dependent gene suppression of pro-death gene.
Also, synaptic NMDA activity and Ca2+ influx activates the Ras/ERK signaling and nuclear CAMKs, which then phosphorylates and activates CREB. The activation of CREB induces the expression of pro-survival genes that protect the neurons against apoptotic insults.
Extra-synaptic NMDA receptors activates pro-death signaling pathways
In contrast to synaptic NMDA receptors, extra-synaptic NMDA receptors are associated with pro-death signaling pathways. When activated, extra-synaptic NMDA receptors attenuate the pro-survival signaling mediated by synaptic NMDA receptors. Extra-synaptic NMDA receptors activation dephosphorylate and inactivate CREB. They also dephosphorylate and inactivate ERk pathway, which prevents the activation of CREB and promote the expression of pro-death gene.
Effect of Cerebrolysin on ischemic Stroke
Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacologic properties similar to those of endogenous neurotrophic factors. It is a lipid-free mixture of seventeen free L-amino acids and twenty-four different low molecular weight neuropeptides obtained by enzymatic proteolysis from the brain of young pigs. It also contains magnesium, phosphorus, potassium and selenium.
Cerebrolysin reduces the number of procoagulants, prothrombotic and proinflammatory mediators, thereby maintaining the normal function and health of the cerebral microvasculature after Ischemia. It counteracts pathological mechanisms by facilitating endogenous repair and regeneration processes. It also protects against pathological events and cascades resulting from trauma or neurodegenerative disease.
It mediates neurogenesis by acting upon the sonic hedgehog signaling pathway and also upon the PI3/Akt kinase pathway.