The Chaperone Inducer U133 Eliminates Anhedonia and Prevents Neurodegeneration in Monoaminergic Emotiogenic Brain Structures in a Preclinical Model of Parkinson's Disease in Aged Rats

Parkinson's disease (PD) is a neurodegenerative disorder mainly diagnosed in elderly patients, which is now considered incurable. To date, there are no effective neuroprotectors suitable to treat PD patients. We have previously demonstrated that U133 therapy, which induces the synthesis of Hsp70 and Hsp40 heat shock proteins in the brain, prevents the development of neurodegeneration in the nigrostriatal system and eliminates sleep disorders in an animal model of PD. In the present study, we assessed the antidepressant properties of preventive U133 therapy, as well as its neuroprotective effect on monoaminergic emotiogenic brain structures in a preclinical model of PD in aged (20-month-old) Wistar rats, created by intranasal administration of the proteasome inhibitor lactacystin. It was found that intraperitoneal U133 administration in aged animals led to a delayed (after 3-7 days) elevation of the Hsp70 (HSPA1) level in the midbrain ventral tegmental area and locus coeruleus. Preventive U133 therapy eliminated the manifestations of depression-like behavior in the form of anhedonia, which develops during the preclinical stage of PD in aged rats. It was established that the antidepressant-like effect of the chaperone inducer U133 is due to the ability of the Hsp70 chaperone to attenuate neurodegeneration and neuroinflammation in the dopaminergic mesolimbic reward system and locus coeruleus noradrenergic system. The data obtained may serve as a fundamental basis for the development of a novel chaperone inducer-based molecular technology for preventive therapy of polyetiological PD and concomitant anhedonia.