Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia

Anil Gulati, Anil Gulati

Abstract

Background: Neurogenesis is most active during pre-natal development, however, it persists throughout the human lifespan. The putative role of mitochondria in neurogenesis and angiogenesis is gaining importance. Since, ETB receptor mediated neurogenesis and angiogenesis has been identified, the role of these receptors with relevance to mitochondrial functions is of interest.

Methods: In addition to work from our laboratory, we undertook an extensive search of bibliographic databases for peer-reviewed research literature. Specific technical terms such as endothelin, mitochondria and neurogenesis were used to seek out and critically evaluate literature that was relevant.

Results: The ET family consists of three isopeptides (ET-1, ET-2 and ET-3) that produce biological actions by acting on two types of receptors (ETA and ETB). In the central nervous system (CNS) ETA receptors are potent constrictors of the cerebral vasculature and appear to contribute in the causation of cerebral ischemia. ETA receptor antagonists have been found to be effective in animal model of cerebral ischemia; however, clinical studies have shown no efficacy. Mitochondrial functions are critically important for several neural development processes such as neurogenesis, axonal and dendritic growth, and synaptic formation. ET appears to impair mitochondrial functions through activation of ETB receptors. On the other hand, blocking ETB receptors has been shown to trigger apoptotic processes by activating intrinsic mitochondrial pathway. Mitochondria are important for their role in molecular regulation of neurogenesis and angiogenesis. Stimulation of ETB receptors in the adult ischemic brain has been found to promote angiogenesis and neurogenesis mediated through vascular endothelial growth factor and nerve growth factor. It will be interesting to investigate the effect of ETBreceptor stimulation on mitochondrial functions in the CNS following cerebral ischemia.

Conclusion: The findings of this review implicate brain ETBreceptors in angiogenesis and neurogenesis following cerebral ischemia, it is possible that the positive effect of stimulating ETB receptors in cerebral ischemia may be mediated through mitochondrial functions.

Figures

Fig. (1)
Fig. (1)
There are two types of ET receptors: ETA and ETB. ETA receptors are found on the vascular smooth muscle and are vasoconstrictor. ETB receptors are identified as ETB1 and ETB2 based upon pharmacological response to RES701. RES701 was found to block ETB1 (located on vascular endothelial cells and function as dilator) but not ETB2 (located on vascular smooth muscle cells and function as constrictor).
Fig. (2)
Fig. (2)
Cerebral ischemia produces a wide variety of changes in the CNS. They can broadly be classified as injury and repair mechanisms. It is our hypothesis that ETB receptor agonist, IRL-1620, may be acting a neuroprotective and may also participate in the repair mechanism following cerebral ischemia. It has been demonstrated that IRL-1620 is both neuroprotective and participates in the repair mechanism in animal model of cerebral ischemia.

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