title: Histopathological and electrophysiological indices of rotenone-evoked dopaminergic toxicity: Neuroprotective effects of acetyl-L-carnitine.
abstract: Exposure to the natural pesticide, rotenone, a potent mitochondrial toxin, leads to degeneration in striatal nerve terminals and nigral neurons. Rotenone-induced behavioral, neurochemical and neuropathological changes in rats mimic those observed in Parkinson's disease (PD). Here, protective effects of acetyl-L-carnitine (ALC) in the brain dopaminergic toxicity after a prolonged exposure to rotenone were evaluated using electrophysiological and immunolabeling methods. Adult, male Sprague-Dawley rats were injected i.p. with rotenone alone (1 mg/kg) or rotenone with ALC (either 10 or 100 mg/kg; ALC10 or ALC100, respectively) once daily on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 and 37. Control rats received either 100mg/kg ALC or vehicle (30% Solutol HS 15 in 0.9% saline) injections. Animals were weighed on injection days and monitored daily. Motor nerve conduction velocity (MCV) was assessed within two days after treatment using compound muscle action potentials (CMAP) detected from the tail muscle through surface receiver electrodes installed around the distal part of the tail. Rats were perfused immediately after testing with 4% paraformaldehyde and immunohistochemical analysis of dopamine transporter (DAT), tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and microglial CD11b marker was performed in the caudate-putamen (CPu) and the substantia nigra pars compacta (SNc) in order to estimate dopaminergic neuronal and transporter damage. Additionally, effects of ALC on preventing microglial or astrocytic hypertrophy were also evaluated. In rats exposed to rotenone and rotenone/ACL10, a significant increases in both proximal (S1) and distal (S2) motor latency and a decrease in MCV were detected in tail nerves (p<0.05). The conduction parameters in rats co-treated with rotenone/ACL100 were not different from control. It was found that 100 mg/kg ALC prevented loss of TH and a decline of DAT level in the midbrain and also prevented the activation of both microglia and astroglia after rotenone treatment. Data indicate neuroprotective effects of ALC in rotenone-evoked dopaminergic neurotoxicity.
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, USA.
authors: S
authors: S
authors: Sarkar
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, USA.
authors: B
authors: B
authors: Gough
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, USA.
authors: J
authors: J
authors: Raymick
authors: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research/FDA, Jefferson, AR, USA.
authors: M A
authors: MA
authors: Beaudoin
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, USA.
authors: S F
authors: SF
authors: Ali
authors: Innovation, Research and Development Nutraceuticals and Carnitines International Division, Sigma-tau BV and Sigma-tau HealthScience BV, Groenewoudsedijk 55, Postbus 2079, 3500 GB Utrecht, The Netherlands.
authors: A
authors: A
authors: Virmani
authors: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, USA. Electronic address: zbigniew.binienda@fda.hhs.gov.
authors: Z K
authors: ZK
authors: Binienda
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000200:Action Potentials; D000818:Animals; D002421:Caudate Nucleus / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation; D009431:Neural Conduction; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010575:Pesticides / Q000633:toxicity*; D011699:Putamen / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity*; D013378:Substantia Nigra / Q000378:metabolism; D013623:Tail / Q000187:drug effects / Q000294:innervation; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D010575:Pesticides; D012402:Rotenone; D000108:Acetylcarnitine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Dopamine transporter (DAT); Midbrain; Peripheral nerves; Rotenone; Tyrosine hydroxylase