White matter damage following systemic injection of the mitochondrial inhibitor 3-nitropropionic acid in rat

Oxidative stress has been implicated as a pathogenic mediator of neuronal p erikarya cell death. Axons and oligodendrocytes. components of white matter , could also be vulnerable to oxidative damage. An experimental model of ox idative stress was induced by systemic injection of 3-nitropropionic acid ( 3-NPA). Animals received an i.p. injection of 10, 15, 20 or 30 mg/kg 3-NPA or vehicle and were killed 24 h later. 3-NPA produced a concentration-depen dent increase in axonal pathology within the striatum reflected by the amou nt of beta -APP and SNAP-25 accumulation. Axonal damage was anatomically co incident with the neuronal lesion. There was no neuronal or axonal damage i n the subcortical white matter or cerebral cortex in any of the animals tre ated with 3-NPA. Manganese superoxide dismutase (Mn-SOD) immunoreactivity w as present in the vehicle and all 3-NPA treated groups. The amount of Mn-SO D cellular staining was concentration-dependently increased within the stri atum supporting a role for oxidative stress in the mechanism of 3-NPA neuro toxicity. Oligodendrocyte-like cells within the subcortical white matter we re immunopositive for calpain-mediated spectrin breakdown products and incr eased in a concentration-dependent manner. Therefore in this experimental m odal, mitochondrial inhibition may lead to the initiation of oxidative stre ss and calpain activation, which could mediate cytoskeletal breakdown in ax ons and oligodendrocytes suggesting an interaction between at least two pat hogenic mechanisms. (C) 2001 Elsevier Science B.V. All rights reserved.