Effects of Sulbactam on behavioral and neuronal deficits in an MPTP-induced Parkinson’s disease rat model

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor impairments, often culminating in dementia. Glutamatergic hyperactivation and γ-aminobutyric acid (GABA) decline contribute to dopaminergic degeneration, highlighting these systems as therapeutic targets. Sulbactam (SUX), a β-lactamase inhibitor, enhances astrocytic glutamate transporter 1 (GLT-1) expression, facilitating glutamate clearance and potentially conferring neuroprotection. We investigated SUX effects on behavioral outcomes, neurotransmitter systems, and neurogenesis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats received bilateral MPTP injections into the substantia nigra pars compacta, followed by daily saline, SUX (50 mg/kg), levodopa (L-dopa; 4 mg/kg), or SUX+L-dopa for 18 or 25 days. Behavioral assessments included spontaneous locomotion, anxiety, working memory, and object recognition. Histological analyses evaluated dopaminergic integrity, subthalamic nucleus activity, neuronal density, neurogenesis, and astrocytic counts. PD rats exhibited motor, emotional, and cognitive deficits, accompanied by dopaminergic neuron loss, subthalamic hyperactivation, and reduced hippocampal neurogenesis. L-dopa improved only object recognition, whereas SUX alone or combined with L-dopa reduced anxiety, enhanced cognition, and mitigated neuronal loss. SUX-treated healthy rats also demonstrated superior memory retention. No significant hippocampal GABAergic alterations were observed. This study provides the first evidence that SUX exerts neuroprotective and pro-neurogenic effects while alleviating emotional and cognitive deficits in PD rats. Restoration of GLT-1-expressing astrocytes may underlie these benefits, supporting SUX as a promising candidate for PD therapy.