RESUMEN
Parkinson's disease (PD) has been linked to exposure to a variety of chemical (e.g., pesticides) and inflammatory agents, which may act cumulatively over time. Finding novel means of limiting pathology associated with toxin exposure would have tremendous clinical importance. To this end, we assessed whether the hematopoietic trophic cytokine, granulocyte macrophage colony stimulating factor (GM-CSF), would inhibit the neurodegenerative effects of the pesticide, paraquat, administered either alone or following priming with the bacterial endotoxin, lipopolysaccharide (LPS). As previously observed, paraquat provoked a modest but significant neurodegenerative effect that was markedly augmented with LPS priming. Central infusion of GM-CSF into the substantia nigra pars compacta (SNc) prevented the loss of SNc dopamine neurons to a degree comparable to that of glial derived neurotrophic factor. Importantly, systemic administration of GM-CSF also had neuroprotective consequences, suggesting that the trophic cytokine can cross the blood brain barrier to promote neuronal survival. Indeed, GM-CSF acted to inhibit the LPS and paraquat induced microglial response, while augmenting astrocyte immunoreactivity within the SNc. Moreover, GM-CSF blunted the paraquat induced reduction of brain derived neurotrophic factor within the hippocampus, as well as in cultured mesencephalic neurons. Although paraquat reduced mesencephalic levels of the anti-apoptotic protein, Bcl-2, GM-CSF had no effect in this regard. Hence, GM-CSF appears to affect inflammatory and/or neuroplastic factors within the SNc that may be linked to neurodegeneration, as well as in other brain regions (hippocampus), which could be important for co-morbid non-motor symptoms in PD. These data suggest that peripheral GM-CSF administration might hold promise as a treatment of PD.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/prevención & control , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Modelos Animales de Enfermedad , Dopamina/fisiología , Herbicidas/toxicidad , Inyecciones Intralesiones/métodos , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Paraquat/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
In addition to nigrostriatal pathology and corresponding motor disturbances, Parkinson's disease (PD) is often characterized by co-morbid neuropsychiatric symptoms, most notably anxiety and depression. Separate lines of evidence indicate that inflammatory processes associated with microglial activation and cytokine release may be fundamental to the progression of both PD and its co-morbid psychiatric pathology. Accordingly, we assessed the contribution of the pro-inflammatory cytokine, interferon-gamma (IFN-gamma), to a range of PD-like pathology provoked by the ecologically relevant herbicide and dopamine (DA) toxin, paraquat. To this end, paraquat provoked overt motor impairment (reduced home-cage activity and impaired vertical climbing) and signs of anxiety-like behavior (reduced open field exploration) in wild-type but not IFN-gamma-deficient mice. Correspondingly, paraquat promoted somewhat divergent variations in neurochemical activity among wild-type and IFN-gamma null mice at brain sites important for both motor (striatum) and co-morbid affective pathologies (dorsal hippocampus, medial prefrontal cortex, and locus coeruleus). Specifically, the herbicide provoked a dosing regimen-dependent reduction in striatal DA levels that was prevented by IFN-gamma deficiency. In addition, the herbicide influenced serotonergic and noradrenergic activity within the dorsal hippocampus and medial prefrontal cortex; and elevated noradrenergic activity within the locus coeruleus. Although genetic ablation of IFN-gamma had relatively few effects on monoamine variations within the locus coeruleus and prefrontal cortex, loss of the pro-inflammatory cytokine did normalize the paraquat-induced noradrenergic alterations within the hippocampus. These findings further elucidate the functional implications of paraquat intoxication and suggest an important role for IFN-gamma in the striatal and motor pathology, as well as the co-morbid behavioral and hippocampal changes induced by paraquat.