Resumo

OBJECTIVES: Many studies have shown that deficits in cognitive functions precede the classical motor symptoms seen in Parkinson’s disease (PD). The cognitive symptoms do not respond to dopaminergic medication and are probably the major current challenge faced in the clinical management of PD. Convergent epidemiological and pre-clinical data suggest that caffeine may confer neuroprotection against the underlying dopaminergic neuron degeneration, and influence the onset and progression of PD. The aim of the present study was to evaluate the potential of caffeine to prevent the cognitive and motor deficits in rats infused with a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an animal model of PD developed by our group. METHODS: Male Wistar rats (n=11-13 per group, 5-6 months-old, 350-400 g) were pre-treated by intraperitoneal (i.p.) route with vehicle (saline) or caffeine (10 mg/kg) once daily during 5 consecutive days. Two hours after the last injection of caffeine, the animals were infused intranasally with a single bilateral dose of MPTP (1 mg/nostril). Animals were evaluated in cognitive (social recognition and step down), locomotor (open-field, activity chambers and rota-rod) and biochemical (western-blot) tests 7 to 30 days after i.n. MPTP infusion. RESULTS: In the social recognition task, MPTP-treated rats spent as much time investigating the juvenile rat during the second encounter as they did in the first exposure, reflecting a clear impairment of the short-term social recognition memory. More importantly, caffeine administration successfully prevented these cognitive deficits induced by i.n. MPTP since the animals behaved in a similar way to control-treated rats, i.e. they were able to recognize the juvenile after an interval of 30 min (investigation time (s): cont:46.9±7.9; caf:46.5±4.0; MPTP:61.4±6.2; caf+MPTP:42.7±6.7). At this time, no significant alterations on the locomotor activity were observed in the open-field. On the other hand, none of the treatments (MPTP or caffeine) altered the long-term memory of rats evaluated in the step-down. At 30 days after i.n. MPTP infusion, a marked reduction in the spontaneous movements of the MPTP-treated rats was observed in activity chambers. Once again, our findings indicated that caffeine was able to prevent these motor impairments induced by MPTP (crossings: cont:138.7±11.6; caf:122.2±13.4; MPTP:86.1±17.9 caf+MPTP:120.4±12.9). Indeed, the motor coordination was not affected by i.n. MPTP administration as indicated by similar latencies to fall in the rota-rod test. Finally, western-blot analysis for the enzyme tyrosine hydroxylase (TH) in the substantia nigra indicated that caffeine was able to prevent the neuronal damage caused by inhalation of MPTP (reduction of TH in relation to control: cont: 0%; caf: 0%; MPTP: 49%; caf+MPTP: 12%). DISCUSSION: These findings reinforce and extend previous literature indicating that caffeine may represent a promising therapeutic tool in PD, thus being the first compound to restore both motor and non-motor early symptoms of PD together with its neuroprotective potential.