Synergistic Effects of Levodopa, Benserazide, and Nortriptyline on Behavioral Impairments and Brain Pathology in an Experimental Rat Model of Parkinson’s Disease

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In addition to postural instability, rigidity, tremor, and bradykinesia, patients will experience depression and/or anxiety at any time during PD. Nortriptyline, as a dual reuptake inhibitor of norepinephrine and serotonin, inhibits alpha-synuclein aggregation and may play an important role in improving the pathological effects of PD. Objective: This study investigated the effects of nortriptyline combined with L-DOPA and benserazide on behavioral, histological, and biochemical changes in a rat model of PD. Methods. Forty-nine rats were randomly assigned to seven groups. Except for the control and sham groups, five other groups underwent stereotactic surgery for the 6-OHDA lesion. We performed a tail suspension swing test and an apomorphine-induced rotation test after 1 week to confirm the PD model. After gradual treatment with three doses (5, 10, and 20 mg/kg) of nortriptyline combined with L-DOPA and benserazide, the elevated plus-maze test and open field test were performed to determine motor activities, anxiety, and depression. Tissue alterations were evaluated through Nissl staining, tyrosine hydroxylase immunohistochemistry, and Golgi-Cox staining, whereas oxidative stress levels were determined by analyzing malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (TAC) markers. Results: Our results demonstrate that 10 mg/kg of nortriptyline in combination with L-DOPA and benserazide significantly improved motor activity and reduced the anxiety- and depression-like behaviors of PD. Histological findings also suggested a protective effect of nortriptyline on dopaminergic neurons in the SNpc. Furthermore, the findings from the antioxidant evaluation and the structure of CA1 hippocampal neurons indicated that a dosage of 10 mg/kg of nortriptyline might provide the greatest supportive benefit. Conclusion: Nortriptyline at 10 mg/kg offers a promising adjunctive therapy for alleviating both motor and nonmotor symptoms of PD. However, higher doses may induce anxiogenic effects, suggesting the need for careful dose optimization.