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.

Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease

“…These results in humans are supported by findings from a recent animal study in which the combination of experimental head trauma and subthreshold paraquat doses led to increased nigrostriatal dopaminergic neuron loss, and greater induction of a-synuclein accumulation and inflammation compared with experimental head trauma treatment alone. 12 Our results for TBI and PD are consistent with findings from previous studies that reported head injuries as being associated with PD.…”

“…12 In the present study, we were unable to address temporality of TBI and paraquat exposures, since pesticide records were only available after 1974. Many of our study participants reported TBIs that had occurred at a young age (mean 5 27 years; range 5 2-82), i.e., during a period when pesticide exposures were not yet recorded in the California system.…”

“…[36][37][38] In experimental animal studies, paraquat exposure can induce reactive oxygen species production in the brain, which may lead to loss of nigral dopaminergic neurons. 39,40 This, combined with recent experimental animal data, 12 suggests that the physiologic process triggered by a head injury may increase the vulnerability of neurons to insults from neurotoxic pesticides, with the combination increasing the risk of PD more than each exposure on its own.…”

“…11 Recently, an animal study demonstrated that even though a single exposure to a mild TBI was sufficient to cause a progressive loss of nigrostriatal dopaminergic neurons, the number of dopaminergic neurons lost was much larger when TBI was accompanied by exposure to paraquat at a dose that by itself did not cause a significant loss of nigrostriatal dopaminergic neurons. 12 Specifically, an insult such as TBI may simply increase the vulnerability of dopaminergic neurons to additional insults, including toxic agents such as pesticides. Herein, utilizing our unique exposure data from a population-based case-control study with a well-characterized PD phenotype, we present evidence that exposure to both TBI and paraquat in humans increases risk for developing PD.…”

Amantadine preserves dopamine level and attenuates depression-like behavior induced by traumatic brain injury in rats

“…These immunological modifications may aggravate the sensitivity of the SN to post-TBI toxic events. Third, other studies have reported that neuronal damage in the SN occurred in the setting of vascular vulnerability and microglial activation following TBI [44,45].…”