| Abstract: | A high percentage of patients with Parkinson’s disease (PD) suffer from not only motor dysfunction but also dementia, Parkinson’s disease dementia (PDD). Hyperactivity of glutamatergic system has been observed in PD. Ceftriaxone, a beta-lactam antibiotic, shows neuroprotection by increasing expression of glutamte transporter 1 (GLT-1). GLT-1, one of the major glutamate transporters on astrocytes, is responsible for reuptake of synaptic glutamate. 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 animal model.
Male Wistar rats were stereotaxically administered with MPTP, bilaterally infused into the substantia nigra pars compacta (SNc), to induce PD rat model. Ceftriaxone (100 and 200 mg/kg/day, i.p.) was administered, starting from either 5 days before or 3 days after the MPTP lesioning. All animals were subjected to behavioral tests and then the brains were taken for histological evaluation. One day after the MPTP lesioning, motor dysfunctions in bar test were observed. Such impairments were spontaneously recovered to control level 7 days after the lesioning. In addition, MPTP lesioning resulted in deficits in working memory and object recognition in the T-maze test and object recognition task, respectively. These deficits were not observed in rats receiving pre- and after-treatment with ceftriaxone.
Histologically, MPTP caused neurodegeneration in nigrostrital dopaminergic system and in the hippocampus and induced hyperactivity of glutamatergic system in the subthalamic nucleous, which were suppressed by ceftreiaxone treatment. Moreover, increase of GLT-1 expression and its colocalization with astrocytes 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. |
