Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate

J Neurochem. 1993 Sep;61(3):1147-50. doi: 10.1111/j.1471-4159.1993.tb03633.x.


Intrastriatal injection of malonate, a reversible inhibitor of succinate dehydrogenase (SDH), produced age-dependent striatal lesions, which were significantly greater in 4- and 12-month-old animals than in 1-month-old animals. Both histologic and neurochemical studies showed that the lesions were significantly attenuated by administration of the noncompetitive NMDA receptor antagonist MK-801. Water-suppressed chemical shift magnetic resonance imaging showed that malonate produces increased striatal lactate concentrations and striatal lesions on T2-weighted scans that were attenuated by MK-801. Neurochemical characterization of the lesions showed significant decreases in markers of medium-sized spiny neurons (GABA and substance P), whereas a marker of medium-sized aspiny neurons (somatostatin) was not different from control values, consistent with an NMDA receptor-mediated mechanism. The effects of intrastriatal injections of malonate on ATP concentrations were compared with those of the irreversible SDH inhibitor 3-nitropropionic acid (3-NP). The ATP depletions following an equimolar injection of malonate were less marked and more transient than those of 3-NP. These results show that the competitive SDH inhibitor malonate produces more transient and milder bioenergetic defects than 3-NP, which are associated with selective activation of NMDA receptors. The results strengthen the possibility that a subtle impairment of energy metabolism may play a role in the pathogenesis of Huntington's disease.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aging / physiology*
  • Animals
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dizocilpine Maleate / pharmacology
  • Lactates / metabolism
  • Lactic Acid
  • Magnetic Resonance Imaging / methods
  • Male
  • Malonates / pharmacology*
  • Mitochondria / drug effects*
  • Neurotoxins / pharmacology*
  • Oxidation-Reduction / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Somatostatin / metabolism
  • Substance P / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Lactates
  • Malonates
  • Neurotoxins
  • Substance P
  • Lactic Acid
  • Somatostatin
  • gamma-Aminobutyric Acid
  • Dizocilpine Maleate
  • Adenosine Triphosphate
  • malonic acid