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Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain.
|Title||Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Journal||Epilepsy & behavior : E&B|
|Date Published||2005 Sep|
Perinatal hypoxia-ischemia (HI) is the most common cause of cerebral palsy, and an important consequence of perinatal HI is epilepsy. Epilepsy is a disorder in which the balance between cerebral excitability and inhibition is tipped toward uncontrolled excitability. Selected neuronal circuits as well as certain populations of glial cells die from the excitotoxicity triggered by HI. Excitotoxicity, a term referring to cell death caused by overstimulation of the excitatory glutamate neurotransmitter receptors, plays a critical role in brain injury caused by perinatal HI. Ample evidence suggests distinct differences between the immature and mature brain with respect to the pathology and consequences of hypoxic-ischemic brain injury. Thus, the intrinsic vulnerability of specific cell types and systems in the developing brain is particularly important in determining the final pattern of damage and functional disability caused by perinatal HI. These patterns of neuronal vulnerability are associated with clinical syndromes of neurologic disorders such as cerebral palsy, epilepsy, and seizures. Recent studies have uncovered important molecular and cellular aspects of hypoxic-ischemic brain injury. The cascade of biochemical and histopathological events initiated by HI can extend for days to weeks after the insult is triggered, which may provide a "therapeutic window" for intervening in the pathogenesis in the developing brain. Activation of apoptotic programs accounts for the majority of HI-induced pathophysiology in neonatal brain disorders. New experimental approaches to protecting brain tissue from the effects of neonatal HI include administration of neuronal growth factors and effective inhibition of the death effector pathways, such as caspase cascade, and their downstream targets, which execute apoptosis and/or induction of their regulatory cellular proteins. Our recent findings that a novel neuronal protein, neuronal pentraxin 1 (NP1), is induced following HI in neonatal brain and that NP1 gene silencing is neuroprotective suggest that NP1 could be a new molecular target in the central neurons for preventing HI injury in developing brain. Most importantly, the specific interactions between NP1 and the excitatory glutamate receptors and their colocalization further implicate a role for this novel neuronal protein in the excitotoxic cascade. Recent experimental work suggests that these approaches may be effective during a longer therapeutic window after the insult, as they are acting on events that are relatively delayed, creating the potential for therapeutic interventions for these lifelong neurological disabilities.
|Alternate Journal||Epilepsy Behav|