Remediation of cellular hypoxic damage by pharmacological agents.
Many known pathological conditions lead to decreases in oxygen supply to various cells. When secondary cellular hypoxia becomes severe, it causes additional cellular damage, aggravating the primary disorder and leading to cell death. Therefore, remediation of secondary hypoxic damage should significantly increase the efficacy of the treatment of primary disease and prevent extensive cellular damage. Analysis of the literature and our experimental data show that the main mechanisms of secondary hypoxic cellular damage include lactate acidosis (lactic acidosis), the boost in free radical processes and the activation of apoptosis and necrosis. These factors result in damage to cellular membranes which in turn further limits oxygen supply leading to augmented hypoxic cellular damage. Therefore, to effectively break this vicious cycle of cellular hypoxia, antihypoxic therapy should simultaneously: (1) mitigate existing cellular hypoxic damage; (2) increase cellular ability to utilize available oxygen; (3) amplify the power of cellular antioxidant defense and (4) prevent hypoxic activation of apoptosis and necrosis. It is clear that such complex task cannot be fulfilled by a single pharmacological agent. Therefore, a complex multi component antihypoxic drug delivery system should be designed to address all the four desiderata indicated above. This review will examine existing pharmaceutical antihypoxic preparations and evaluate the new methods for the pharmacological remediation of cellular hypoxic damage and propose future directions for the design of the needed drug delivery systems.
Minko
Tamara
T
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. minko@rci.rutgers.edu
Wang
Yang
Y
Pozharov
Vitaly
V
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000187:drug effects; D015398:Signal Transduction
D000975:Antioxidants