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Early gene induction by L-DOPA in the striatum of dopamine denervated rats represents a useful way to study long-term modifications produced by this drug. The effects of acute and subchronic L-DOPA administration on zif-268 mRNA expression were compared in 6-hydroxydopamine-lesioned rats. Rats received a subchronic intermittent L-DOPA (6 mg/kg) treatment, which produces behavioural sensitization, a correlate of dyskinetic movements. Three days after interruption of subchronic treatment, zif-268 mRNA was evaluated after an L-DOPA challenge. Zif-268 mRNA levels increased in the lesioned dorsolateral striatum after either acute or subchronic L-DOPA administration. Double labelling of striatal cells with zif-268 and enkephalin or dynorphin mRNA probes was performed to assess neuronal activation in the indirect and direct output pathway. Single acute L-DOPA significantly increased zif-268 in all striatal neurons reflecting a hyperresponsiveness of dopamine-depleted striatum. After subchronic L-DOPA, zif-268 mRNA labelling was still increased in the striatonigral pathway, limited to dynorphin(+) neurons, whereas in all other neurons it was similar to the control value. Results suggest that striatal neurons responding to acute L-DOPA differ from those responding to subchronic L-DOPA. L-DOPA-induced behavioural sensitization was associated to a down-regulation in the responsiveness of striatopallidal and striatonigral dynorphin(-) neurons, whereas in striatonigral neurons containing dynorphin a hyperresponsiveness to L-DOPA was observed. High levels of zif-268, together with a persistent hyperresponsiveness of striatonigral dymorphinergic neurons and hyporesponsiveness of striatopallidal neurons, by creating an unbalanced state of striatal efferent neurons, may be implicated in dyskinetic movements observed in Parkinson's disease (PD).

Parkinson's disease (PD) is amongst the most frequent neurodegenerative disorders, the main pathologic hallmark of which is the degeneration of the substantia nigra pars compacta. Damage to multiple cellular components, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and proteasomal dysfunction, contribute to the progression of the neurodegenerative process. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, mainly thiazolidinediones, pioglitazone and rosiglitazone, have been successfully tested for their neuroprotective potential in PD experimental models, although the cellular target and underlying mechanism are currently a matter of debate. While the anti-inflammatory activity and attenuation of microgliosis have been proposed as a main mechanism of neuroprotection, other cellular targets might be involved, such as mitochondrial proteins controlling cellular bioenergetic and oxidative stress. Here, the current evidence of neuroprotection by PPAR-γ agonists in in vitro and in vivo experimental PD models is reported. Moreover, cellular pathways which have been investigated as potential targets of neuroprotection are reviewed. Taken together, the available data suggest that simultaneous targeting of multiple dysfunctional pathways may underlie the potent neuroprotective activity displayed by PPAR-γ agonists.

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