Effects of adamantane derivatives on behavioral activity of mice with different stages of experimental parkinsonian syndrome
A key element in the pathogenesis Parkinson's disease (PD) is death of dopaminergic neurons in substantia nigra, which leads to a sharp decrease in striatal concentration of dopamine. Long-term use of levodopa-containing drugs results in severe side effects and the disease progression. A new antiparkinsonian drug, the adamantine derivative, hemantane (N-(2-adamantyl)-hexamethyleneimine hydrochloride), has neuroprotective and anti-inflammatory features. Objective: To compare effects of hematane and amantadine on locomotor activity of mice at different stages of the parkinsonian syndrome (PS). Methods. Experiments were performed on C57Bl/6 male mice (n = 98) aged 3-4 months and weighing 22-24 g. The stages (early stage, mid-stage, and advanced stage) of parkinsonian syndrome (PS) were simulated in C57Bl/6 mice by intraperitoneal injections of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), either at a single dose of 16 mg/kg, 30 mg/kg, and 40 mg/kg, or repeatedly, 4 times at 12 mg/kg or 4 times at 20 mg/kg at 2-h intervals. Gimantan and amantadine hydrochloride (midantan) were administered to animals at a single dose of 20 mg/kg 30 minutes prior to MPTP administration or 4 times with the repeated administration of the neurotoxin. The development of PS was detected by muscle rigidity and changes in motor activity. Results. Administration of either hematane or amantadine increased the distance traveled and the number of rearings, and also reduced severity of the rigidity and impairment of movement coordination when PS was induced by a single injection of MPTP 16 mg/kg and repeated injections of MPTP 4 × 12 mg/kg. Furthermore, the effects of gimantan were more pronounced in comparison with the effects of amantadine. The antiparkinsonian effect of both drugs was weaker at the mid-stage of PS caused by a single injection of MPTP 30 mg/kg and was absent at the advanced stage of PS caused by repeated injections of MPTP 4 × 20 mg/kg. Conclusion. Compared to amantadine, the prior administration of gimantan more effectively prevented the decrease in motor activity, impaired coordination of movements and development of stiffness in animals at the early stage of PS.