The effect of postnatal age on L-2-chloropropionic acid-induced cerebellar granule cell necrosis in the rat.
L-2-Chloropropionic acid (L-2-CPA) selectively damages the cerebellum in adult rats. The rat cerebellum continues to develop postnatally during the first 4 weeks of life. In this study we examined the neurotoxic effect on rats of increasing postnatal age. Daily oral dosing of rats aged 56 days with 250 mg/kg per day of L-2-CPA for 3 days produced necrosis to neurons in the cerebellar granule cell layer and to neurons in the medial/ventral region of the habenular nucleus. Rats aged 22 days were resistant to the cerebellar toxicity while rats aged 32 days and older were sensitive. A single large oral dose of 500 or 750 mg/kg L-2-CPA produced no clinical signs of neurotoxicity or lesions in the cerebellum 48 h after dosing in 22-day-old rats. Daily dosing of 22-day-old rats at 250 mg/kg per day L-2-CPA for 10 days also produced no signs of neurotoxicity or reduction in body weight gain, although histological examination of the brain revealed slight neuronal cell necrosis in the granule cell layer of the cerebellum with a minimal effect in the medial/ventral region of the habenular nucleus. In contrast, daily dosing of rats aged 32, 38, 48 and 58 days with 250 mg/kg per day of L-2-CPA for 3 days produced clear signs of neurotoxicity which were associated with reduced body weight gain and loss of hindlimb function. In these rats there was clear evidence of neuronal cell loss in the cerebellar granule cell layer and medial/ventral region of the habenular nucleus. This study showed that the postnatal developing cerebellum is resistant to L-CPA-induced injury in rats up to 25 days of age, but becomes vulnerable to the toxicity by 32 days of age. The basis for the resistance of the developing cerebellum to L-CPA is discussed.
Lock
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Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK. ted.lock@ctl.zeneca.com
Gyte
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Duffell
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Wyatt
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D000367:Age Factors; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D003594:Cytoplasmic Granules / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D019262:Habenula / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D006843:Hydrocarbons, Chlorinated; D008297:Male; D018908:Muscle Weakness / Q000139:chemically induced / Q000503:physiopathology; D009336:Necrosis; D011422:Propionates / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D014018:Tissue Distribution; D015430:Weight Gain / Q000187:drug effects
D006843:Hydrocarbons, Chlorinated; D011422:Propionates; C021974:2-chloropropionic acid