Balázs Gaszner

Numerous in vitro and in vivo models of Parkinson’s disease (PD) demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP) conveys its strong neuroprotective actions mainly via its specific PAC1 receptor (PAC1R) in models of PD. We recently described the decrease in PAC1R protein content in the basal ganglia of macaques in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD that was partially reversed by levodopa therapy. In this work, we tested whether these observations occur also in the rotenone model of PD in the rat. The rotarod test revealed motor skill deterioration upon rotenone administration, which was reversed by benserazide/levodopa (B/L) treatment. The sucrose preference test suggested increased depression level while the open field test showed increased anxiety in rats rendered parkinsonian, regardless of the received B/L therapy. Reduced dopaminergic cell count in the substantia nigra pars compacta (SNpc) diminished the dopaminergic fiber density in the caudate-putamen (CPu) and decreased the peptidergic cell count in the centrally projecting Edinger–Westphal nucleus (EWcp), supporting the efficacy of rotenone treatment. RNAscope in situ hybridization revealed decreased PACAP mRNA (Adcyap1) and PAC1R mRNA (Adcyap1r1) expression in the CPu, globus pallidus, dopaminergic SNpc and peptidergic EWcp of rotenone-treated rats, but no remarkable downregulation occurred in the insular cortex. In the entopeduncular nucleus, only the Adcyap1r1 mRNA was downregulated in parkinsonian animals. B/L therapy attenuated the downregulation of Adcyap1 in the CPu only. Our current results further support the evolutionarily conserved role of the PACAP/PAC1R system in neuroprotection and its recruitment in the development/progression of neurodegenerative states such as PD.

Middle-aged obesity and aging cachexia present healthcare challenges. Central responsiveness to body-weight-reducing mediators, e.g., to leptin, changes during aging in a way, which may promote middle-aged obesity and aging cachexia. Leptin is connected to urocortin 2 (Ucn2), an anorexigenic and hypermetabolic member of the corticotropin family. We aimed to study the role of Ucn2 in middle-aged obesity and aging cachexia. The food intake, body weight and hypermetabolic responses (oxygen consumption, core temperature) of male Wistar rats (3, 6, 12 and 18 months) were tested following intracerebroventricular injections of Ucn2. Following one central injection, Ucn2-induced anorexia lasted for 9 days in the 3-month, 14 days in the 6-month and 2 days in the 18-month group. Middle-aged 12-month rats failed to show anorexia or weight loss. Weight loss was transient (4 days) in the 3-month, 14 days in the 6-month and slight but long-lasting in the 18-month rats. Ucn2-induced hypermetabolism and hyperthermia increased with aging. The age-dependent changes in the mRNA expression of Ucn2 detected by RNAscope in the paraventricular nucleus correlated with the anorexigenic responsiveness. Our results show that age-dependent changes in Ucn2 may contribute to middle-aged obesity and aging cachexia. Ucn2 shows potential in the prevention of middle-aged obesity.