Drugs of abuse-induced hyperthermia, blood-brain barrier dysfunction and neurotoxicity: neuroprotective effects of a new antioxidant compound H-290/51

Curr Pharm Des. 2007;13(18):1903-23. doi: 10.2174/138161207780858375.

Abstract

The psychostimulants, morphine and methamphetamine are well known drugs of abuse that induce brain pathology and/or neurodegeneration resulting in a huge burden on our society. The possible mechanisms of psychostimulants induced neuropathology and neurodegeneration are still not well known. The drugs of abuse results in profound hyperthermia and widespread alterations in neurochemical metabolism in the central nervous system (CNS). It appears that psychostimulants induced hyperthermia and/or release of neurochemicals influence the blood-brain barrier (BBB) dysfunction leading to brain pathology. The drugs of abuse also induce oxidative stress resulting in generation of free radicals and lipid peroxidation. Thus, further research is needed to understand the basic function of BBB disruption and temperature regulation by psychostimulants and to modify them pharmacologically to attenuate brain dysfunction and neuropathology. This review is focused on the problems of morphine and methamphetamine induced hyperthermia and their effects on breakdown of the BBB function leading to brain damage. Work done in our laboratory suggest that hyperthermia caused by these drugs is responsible for BBB disruption and neurodegeneration. This hypothesis is further supported by our observation that pretreatment with a potent antioxidant compound H-290/51 attenuates the BBB disruption and induces marked neuroprotection following morphine induced withdrawal and methamphetamine induced neurotoxicity. The possible mechanisms and functional significance of these findings are discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amphetamine-Related Disorders / complications
  • Amphetamine-Related Disorders / physiopathology
  • Animals
  • Antioxidants / pharmacology*
  • Antioxidants / therapeutic use
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / physiopathology
  • Central Nervous System Stimulants / adverse effects
  • Fever / etiology
  • Fever / metabolism
  • Fever / pathology
  • Fever / physiopathology
  • Fever / prevention & control*
  • Humans
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Methamphetamine / adverse effects
  • Morphine Dependence / complications
  • Morphine Dependence / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / metabolism
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / physiopathology
  • Neurotoxicity Syndromes / prevention & control*
  • Neurotransmitter Agents / metabolism
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / pathology
  • Substance Withdrawal Syndrome / physiopathology
  • Substance Withdrawal Syndrome / prevention & control*
  • Substance-Related Disorders / complications*
  • Substance-Related Disorders / metabolism
  • Substance-Related Disorders / pathology
  • Substance-Related Disorders / physiopathology

Substances

  • Antioxidants
  • Central Nervous System Stimulants
  • H290-51
  • Indoles
  • Neuroprotective Agents
  • Neurotransmitter Agents
  • Reactive Oxygen Species
  • Methamphetamine