title: Systemic or local administration of azide produces striatal lesions by an energy impairment-induced excitotoxic mechanism.
abstract: Sodium azide is an inhibitor of cytochrome oxidase which produces selective striatal lesions in both rodents and primates. In the present study we investigated the neurochemical and histologic effects of both intrastriatal and systemic administration of sodium azide, as well as the age dependence and mechanism of the lesions. Intrastriatal administration of sodium azide produced dose-dependent lesions. Neurochemical and histologic evaluation showed that markers of both spiny projection neurons (GABA, substance P) and aspiny interneurons (somatostatin, neuropeptide Y, NADPH-diaphorase) were equally affected. Subacute systemic administration of sodium azide resulted in lesions with a similar neurochemical profile; however, in contrast to intrastriatal injections there was sparing of dopaminergic striatal afferents. Prior decortication significantly attenuated lesions produced by intrastriatal administration of sodium azide, consistent with an excitotoxic process. Chronic administration of sodium azide for 1 month lead to striatal neuropathological changes. Lesions produced by intrastriatal administration of sodium azide in 1-, 4-, and 12-month-old animals showed age dependence. Both freeze-clamp measurements and chemical-shift magnetic resonance spectroscopy confirmed that sodium azide impairs oxidative phosphorylation in the striatum following either intrastriatal or systemic administration. These results show that the striatum is particularly vulnerable to oxidative stress produced by sodium azide, and that it produces striatal lesions by a secondary excitotoxic mechanism.
authors.affiliation: Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
authors.forename: E
authors.initials: E
authors.lastname: Brouillet
authors.forename: B T
authors.initials: BT
authors.lastname: Hyman
authors.forename: B G
authors.initials: BG
authors.lastname: Jenkins
authors.forename: D R
authors.initials: DR
authors.lastname: Henshaw
authors.forename: J B
authors.initials: JB
authors.lastname: Schulz
authors.forename: P
authors.initials: P
authors.lastname: Sodhi
authors.forename: B R
authors.initials: BR
authors.lastname: Rosen
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000818:Animals; D001386:Azides / Q000008:administration & dosage / Q000633:toxicity*; D001679:Biogenic Amines / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007773:Lactates / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008845:Microinjections; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D019810:Sodium Azide; D013004:Somatostatin / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001386:Azides; D001679:Biogenic Amines; D005904:Glial Fibrillary Acidic Protein; D007773:Lactates; D009478:Neuropeptide Y; D009479:Neuropeptides; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D013373:Substance P; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D019810:Sodium Azide; D009252:NADPH Dehydrogenase; D004298:Dopamine; D006719:Homovanillic Acid