ENERGETIC DYSFUNCTION IN QUINOLINIC ACID-LESIONED RAT STRIATUM

Impairment of mitochondrial energy metabolism may contribute to the se lective neuronal degeneration observed in Huntington's disease and oth er neurodegenerative disorders. Intrastriatal injection of the excitot oxin, quinolinic acid, produces a pattern of neuronal death similar to that seen in Huntington's disease. However, little is known about the effects of quinolinic acid on striatal energetics. In the present wor k, time-dependent changes in energy metabolism caused by injection of quinolinic acid into rat striatum were examined. Oxygen consumption by free and synaptic mitochondria was quantified and correlated with the concentrations of nucleotides and amino acids at different times afte r injection. Compared with saline-treated controls, a decrease in ADP- stimulated (state 3)to basal (state 4)oxygen consumption (respiratory control ratio) by free mitochondria was apparent in quinolinic acid-in jected striata as early as 6 h after treatment. No significant changes were seen in nucleotide concentrations at this time. By 12 h after in jection, the decline in the respiratory control ratio was more pronoun ced (45%), and reductions in ATP, NAD, aspartate, and glutamate (30-60 %) were also observed. These results show that injection of quinolinic acid in vivo produces progressive mitochondrial dysfunction, which ma y be a common and critical event in the cell death cascade initiated i n Huntington's disease and in animal models of this neurodegenerative disorder. The indicators of mitochondrial function examined in this st udy, therefore, may be useful in evaluating the efficacy of neuroprote ctive agents.