Mitochondrial involvement in transhemispheric diaschisis following hypoxia–ischemia: Clomethiazole-mediated amelioration

• Published in: Neuroscience Vol. 144; no. 2; pp. 547 - 561
• Main Authors: Clarkson, A.N, Clarkson, J, Jackson, D.M, Sammut, I.A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 19.01.2007; Elsevier
• Subjects: aconitase; Animals; Animals, Newborn; ATP synthase; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain - ultrastructure; Chlormethiazole - therapeutic use; citrate synthase; Cytokines - metabolism; Functional Laterality - drug effects; Fundamental and applied biological sciences. Psychology; Immunoassay; In Vitro Techniques; inflammation; Ischemia - drug therapy; Ischemia - pathology; Male; Mitochondria - drug effects; Mitochondria - pathology; Mitochondria - physiology; mitochondrial enzymes; Models, Biological; neurodegeneration; Neurology; Neuroprotective Agents - therapeutic use; Oxidative Stress - drug effects; Oxygen Consumption - drug effects; Rats; Rats, Wistar; Time Factors; Vertebrates: nervous system and sense organs; HI; NO; eNOS; TTC; PND; neurodegeneration; endogenous nitric oxide synthase; postnatal-day; TNF; aconitase; inducible nitric oxide synthase; citrate synthase; respiratory control indices; BSA; ATP synthase; inflammation; GM-CSF; reactive oxygen species; iNOS; ONOO; nitric oxide synthase; interleukin; mitochondrial enzymes; granulocyte macrophage colony-stimulating factor; clomethiazole; electron transport chain; hypoxia-ischemia; nitric oxide; IL; peroxynitrite; CMZ; NOS; tumor necrosis factor; ETC; ROS; RCI; 2,3,5-triphenyltetrazolium chloride; bovine serum albumin; Clomethiazole; Oxygen; Enzyme; Cardiovascular disease; Environmental factor; Lyases; Inflammation; Aconitate hydratase; Synthase; Mitochondria; Ischemia; Hypoxia; Degeneration; Carbon-oxygen lyases; ATP; Hydro-lyases
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2006.09.040

Abstract Mitochondria play a central role in both the physiological and pathophysiological regulation of cell survival/death. Increasing evidence places mitochondrial dysfunction at the center of many neuropathological conditions. The present study investigates the extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues in a rat model of hypoxia–ischemia (HI). We hypothesized that; mitochondrial dysfunction in situ may be prevented by treatment with clomethiazole (CMZ), a GABAA receptor agonist. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-day post-HI revealed a marked decrease in activity from ipsilateral cortical and hippocampal regions ( P <0.001). In addition, small changes were seen in contralateral cortical and hippocampal tissues as well as in the cerebellum at 3-days ( P <0.05). Assessment of the mitochondrial electron transport chain (complexes I–V), and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed mitochondrial impairment in ipsilateral regions following HI. Complexes I, II–III, V and citrate synthase were also impaired in contralateral regions and cerebellum 3-days post-HI. Treatment with CMZ (414 mg/kg/day via minipumps) provided marked protection to all aspects of neuronal tissue assessed. Circulating cytokine (interleukin [IL]-1α, IL-1β, tumor necrosis factor [TNF]-α, granulocyte macrophage colony-stimulating factor [GM-CSF], IL-4 and IL-10) levels were also assessed in these animals 3-days post-HI. Plasma IL-1α, IL-1β, TNF-α and GM-CSF levels were significantly increased post-HI. Treatment with CMZ ameliorated the increases in IL-1α, IL-1β, TNF-α and GM-CSF levels while increasing plasma IL-4 and IL-10 levels. This study provides evidence of the extent of mitochondrial damage following an HI-insult. In addition, we have shown that protection afforded by CMZ extends to preservation of mitochondrial function and integrity via anti-inflammatory mediated pathways.