Central Nervous System Agents in Medicinal Chemistry

(Formerly Current Medicinal Chemistry - Central Nervous System Agents)


Encephalopathy: A Vicious Cascade Following Forebrain Ischemia and Hypoxia

Author(s): Baowan Lin

Affiliation: Department of Neurology [D4-5], University of Miami School of Medicine, PO Box 016960, Miami, Florida 33101, USA.


Post ischemic/hypoxic encephalopathy is a progressive and widespread damage syndrome in human brain, which includes production of new ischemic foci as well as neurodegeneration associated with accumulation of amyloid protein (Aβ), which emerges within days after the primary ischemic or hypoxic ictus. Patients may suddenly suffer severe dementia and Parkinson’s syndrome after a symptom-free period averaging 2 weeks following resuscitation. Death of neurons in the cortex, limbic system, globus pallidus (GP) and substantia nigra (SN) and damage to white matter are responsible. From experimental studies in animals evidence is obtained to reveal the mechanisms. Injured endothelia and activated platelets lead to secondary injury via thrombosis and vasoconstriction resulting in infarction and new foci of necrosis. Blood-brain barrier (BBB) breakdown allows penetration of blood-borne toxic substances into brain resulting in neuronal degeneration and enhanced inflammatory destruction. These secondary injuries happen within two weeks after moderate global ischemia. As these pathological changes cycle between the vascular and neuronal compartments, the damage expands and worsens. Aβ, β amyloid precursor protein (βAPP) and the inflammation mediator cyclooxygenase-2 (COX2) as well as γ-aminobutyric acid (GABA) system degeneration participate in producing secondary injury. Thus, implementing multi-targeted prophylaxis before or at the brain-at-risk stage is desirable. A combination of protecting endothelia, inhibiting platelet activity and improving cerebral circulation is a fundamental strategy to block this vicious cascade, thereby ameliorating or preventing the encephalopathy.

Keywords: Asphyxia, CO, dementia, heart attack, ischemia, Parkinsonism

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Article Details

Page: [57 - 70]
Pages: 14
DOI: 10.2174/1871524911313010008