Microglial activation with a tight control of IL-1 protein production in a rat model of Parkinson´s disease

DEPINO A; EARL C; KACZMARCZYK E; BESEDOVSKY H; DEL REY A; OERTEL WH; PITOSSI F

Praga, República Checa

Congreso; Sixth International Brain Research Organization World Congress of Neuroscience; 2003

International Brain Research Organization

Microglial activation has been associated with the production of cytokines in different models in vitro and in vivo. By these means, cytokines have been proposed to mediate neurodegenerative or neuroprotective effects. Nevertheless, recent reports have demonstrated that in models of chronic neurodegeneration microglial activation without cytokine production can be observed (Perry et al. (2002), Curr Opin Neurol 15(3): 349-54). We decided to study whether microglial activation correlates with cytokine production in an animal model of Parkinson´s disease induced by the striatal injection of 6-hydroxydopamine. We investigated the mRNA levels of IL-1α, IL-1β, IL-1ra and TNF-α by competitive RT-PCR along with the glial activation by immunohistochemistry, in striata and substantia nigra (SNi) of lesioned and control animals 2, 6, 12 and 30 days after the injection. In the striata, we observed a strong activation of glial cells and the presence of macrophages in the injected site regardless the treatment. IL-1α, IL-1β and IL-1ra mRNA levels presented no differences among treatments. On the other hand, only activated microglia was detected in the lesioned SNi, reaching a maximum at 12 days. We observed an increment of IL-1α and IL-1β mRNA levels 30 days after lesion in the ipsilateral SNi, but no changes in IL-1ra mRNA. TNF-α was not detected. Surprisingly, no changes at the protein level were detected for IL-1α or IL-1β at this time point although the injection of an adenoviral vector that expresses human IL-1β leads to a similar increment in rat IL-1β mRNA and protein. These results show that activated microglia could be tightly controlled to avoid cytokine production during neurodegeneration. We suggest that although the neuronal death does not induce the production of pro-inflammatory cytokines, it ¨primes¨ microglia making them susceptible to additional stimuli that could induce these glial cells to produce such cytokines and influence disease progression.