Energetic Dysfunction in Quinolinic Acid‐Lesioned Rat Striatum

Abstract

Impairment of mitochondrial energy metabolism may contribute to the selective neuronal degeneration observed in Huntington's disease and other neurodegenerative disorders. Intrastriatal injection of the excitotoxin, 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 work, 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 after 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-injected striata as early as 6 h after treatment. No significant changes were seen in nucleotide concentrations at this time. By 12 h after injection, the decline in the respiratory control ratio was more pronounced (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 may be a common and critical event in the cell death cascade initiated in Huntington's disease and in animal models of this neurodegenerative disorder. The indicators of mitochondrial function examined in this study, therefore, may be useful in evaluating the efficacy of neuroprotective agents.

Metabolic changes in quinolinic acid‐lesioned rat striatum detected non‐invasively by in vivo 1H NMR spectroscopy

“…Second, the scatter in the GABA measurements can be explained by the difficulties involved in detecting small changes in the GABA signal, that is comparatively weakly represented in the 1 H spectrum, even at 9.4 T. The decreased concentration of Tau (Ϫ14 Ϯ 6)% observed in our study is in agreement with the decrease in extracellular Tau concentration measured by microdialysis (Bockelmann et al, 1998) and with an 46% decrease in Tau concentration measured 7 days after 240 nmol QA (Ellison et al, 1987). Phosphocreatine was decreased and lactate was increased in the QA lesions relative to the contralateral striatum in five of seven rats, which supports the notion that QA induces impairments in energy metabolism (Bordelon et al, 1997).…”

“…The decreased NAA concentration in the QA lesion can by explained by the decreased NAA concentration in excitotoxically-impaired neurons as well as the selective loss of neurons in the lesion. The increased glutamine and decreased glutamate concentrations are in agreement with the results of chemical analysis of tissue extracts performed 12 hr after QA injection (Bordelon et al, 1997), although we did not observe such a substantial decrease in glutamate (Bordelon et al, 1997). The QA dose and the post-injection time, however, were not identical.…”

“…The somewhat smaller decrease in our study (Table I) probably reflects the smaller dose (150 nmol) used. These results strongly point to the involvement of oxidative stress possibly associated with impaired mitochondrial function in the pathogenesis of the toxin model of HD (Bordelon et al, 1997). Decreased GSH in QA lesions is also consistent with the observation that antioxidant treatment (Koroshetz et al, 1997;Matthews et al, 1998a) protected striatal neurons against excitotoxic insult, which supports the hypothesis that free radicals contribute to excitotoxic neuronal injury (Nakao et al, 1996).…”

“…Methods used to assess metabolite concentration changes in excitotoxic lesions include immunohistochemistry (Nakao et al, 1996), radioimmunoassay (Beal et al, 1986), freeze clamp technique followed by tissue extrac-tion and HPLC analysis (Beal et al, 1986;Bordelon et al, 1997), microelectrodes (Bordelon et al, 1998), and microdialysis (Reynolds et al, 1997), all of which are invasive and thus not very well suited for longitudinal studies. Non-invasive microPET imaging was used to assess time course of alternations in energy utilization and dopamine receptors in QA-lesioned rat striatum (Araujo et al, 2000).…”

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

“…NMDA and glutamate) in the context of energy depletion [22,23] . We previously showed that chronic exposure to QUIN in pathophysiologically appropriate concentrations causes ultrastructural changes in cultured human neurons [24] .…”