title: Traumatic brain injury in adult rats causes progressive nigrostriatal dopaminergic cell loss and enhanced vulnerability to the pesticide paraquat.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk.
authors.affiliation: Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Che Brown
authors.initials: CB
authors.lastname: Hutson
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Lazo
authors.forename: Farzad
authors.initials: F
authors.lastname: Mortazavi
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Giza
authors.forename: David
authors.initials: D
authors.lastname: Hovda
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D006540:Herbicides / Q000494:pharmacology*; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010269:Paraquat / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D006540:Herbicides; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat; D004298:Dopamine