The effect of postnatal age on L-2-chloropropionic acid-induced cerebellargranule cell necrosis in the rat

L-2-Chloropropionic acid (L-2-CPA) selectively damages the cerebellum in ad ult rats. The rat cerebellum continues to develop postnatally during the fi rst 4 weeks of life. In this study we examined the neurotoxic effect on rat s 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 cerebella r 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 neurot oxicity 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 al so produced no signs of neurotoxicity or reduction in body weight gain, alt hough histological examination of the brain revealed slight neuronal cell n ecrosis in the granule cell layer of the cerebellum with a minimal effect i n the medial/ventral region of the habenular nucleus. In contrast, daily do sing 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 ther e was clear evidence of neuronal cell loss in the cerebellar granule cell l ayer and medial/ventral region of the habenular nucleus. This study showed that the postnatal developing cerebellum is resistant to L-CPA-induced inju ry 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 t o L-CPA. is discussed.