Glutamatergic hyperactivity plays an important role in pathophysiology of Parkinson’s disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and shows neuroprotection. This study was aimed at clarifying whether ceftriaxone prevents or reverses behavioral and neuronal deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model.
Male Wistar rats were used in this study. A set of animals received ceftriaxone (100 and 200 mg/kg/day, i.p.) treatment, starting from either 5 days before or 3 days after the MPTP lesioning. Starting on the next day (day 1) of MPTP lesioning, the rats underwent a bar-test on days 1-7, a T-maze test on days 8-10, and an object recognition test on days 12-14. On the next day of behavioral test the brains were taken for histological evaluation. Another set of animals was sacrificed on the 3rd or 15th day after the brain surgery, without receiving behavioral test, for histological analysis.
Dopaminergic degeneration in the SNc and striatum was observed on the 3rd day after the MPTP lesioning and was not recovered till the 15th day. Behaviorally, one day after the MPTP lesioning, motor dysfunctions in bar test were observed. Such impairments were spontaneously recovered to control level in a week. In addition, MPTP lesioning resulted in deficits in working memory and object recognition in the T-maze test and object recognition task, respectively. These cognitive deficits were not observed in rats both receiving pre- and post-treatment with ceftriaxone. MPTP lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, these changes were suppressed by ceftriaxone treatment. Moreover, increase of GLT-1 expression and its colocalization with astrocyte were observed in the striatum and hippocampus. These results suggest that, by increasing GLT-1 expression, ceftriaxone prevents and reverses PD-related neurodegeneration and cognitive dysfunctions. Thus, ceftriaxone may have clinical potential for prevention and treatment of dementia associated with PD.
Keywords: Parkinson’s disease, glutamatergic hyperactivity, glutamate transporter 1, ceftriaxone, dementia, neuroprotection, cognition