| Abstract: | A decrease in activity of ubiquitin proteasome system results in accumulation of toxic forms of protein and cell degeneration, including dopamine (DA)-ergic neurons in the substantia nigra; these neurons are remarkable for their low proteolytic activity of proteosomes that makes them more vulnerable, especially when subjected to the neurotoxin action or Parkinson's disease (PD). The goal of the present study is to develop a model on the basis of inhibition of proteasome activity of nigral cell degeneration which is not accompanied by disturbances in motor behavior but leads to changes in sleep-wake cycle characteristic of the non-motor behaviour. We determined the optimal dose of natural inhibitor of proteasome lactacystin (0.4 mkg) and developed a preclinical model of PD in Wistar rats. We established that on the 14th day following lactacystin double (with one-week interval) bilateral injection into the substantia nigra the developing effects involved 28 % degeneration of DA-ergic neurons in the compact part of the substantia nigra, absence of disorders in motor behaviour, and increase in the total time of rapid eye movement sleep by 37 % at the second half of inactive day phase. These data and an increase in the level of key enzyme of DA synthesis tyrosine hydroxylase (TH) in survived neurons in the substantia nigra as well as the presence of the inverse correlation dependency (r = -0.8, p < 0.01) between the number of survived neurons and the level of TH inside them suggest a hypothesis that the increase in the duration of rapid eye movement sleep could be a non-motor marker of the preclinical stage of PD reflecting a reservation of compensatory potentials in the nigrostriatal system. |
