ro13-9904 and Parkinsonian-Disorders

Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD.

Topics: Animals; Astrocytes; Brain; Ceftriaxone; Disease Models, Animal; Dopaminergic Neurons; Excitatory Amino Acid Transporter 2; Male; Maze Learning; Motor Activity; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rats, Wistar; Recognition, Psychology

Both ceftriaxone (CEF) and erythropoietin (EPO) show neuroprotection and cognitive improvement in neurodegenerative disease. The present study was aimed at clarifying whether combined treatment with CEF and EPO (CEF+EPO) had superior neuroprotective and behavioral effects than treatment with CEF or EPO alone in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) rat model. The rats were injected with CEF (5 mg/kg/day), EPO (100 IU/kg/day), or CEF+EPO after MPTP lesioning and underwent the bar-test, T-maze test, and object recognition test, then the brains were taken for histological evaluation. MPTP lesioning resulted in deficits in working memory and in object recognition, but the cognitive deficits were markedly reduced or eliminated in rats treated with CEF or CEF+EPO, with the combination having a greater effect. Lesioning also caused neurodegeneration in the nigrostriatal dopaminergic system and the hippocampal CA1 area and these changes were reduced or eliminated by treatment with CEF, EPO, or CEF+EPO, with the combination having a greater effect than single treatment in the densities of DAergic terminals in the striatum and neurons in the hippocampal CA1 area. Thus, compared to treatment with CEF or EPO alone, combined treatment with CEF+EPO had a greater inhibitory effect on the lesion-induced behavioral and neuronal deficits. To our knowledge, this is the first study showing a synergistic effect of CEF and EPO on neuroprotection and improvement in cognition in a PD rat model. Combined CEF and EPO treatment may have clinical potential for the treatment of the dementia associated with PD.

Topics: Animals; Antiparkinson Agents; Brain; Ceftriaxone; Cognition; Dementia; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Male; Memory; Neuroprotective Agents; Nootropic Agents; Parkinsonian Disorders; Pyramidal Cells; Rats, Wistar; Treatment Outcome

Glutamate receptor antagonists can improve the symptoms of Parkinson's disease (PD) and reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in both animal models and humans, but usually produce intolerable side effects. Recent evidence suggests that upregulation of the major glutamate transporter, GLT-1, by the β-lactam antibiotic, ceftriaxone, can increase the removal of synaptic glutamate without producing noticeable side effects, and may provide an effective alternative to receptor antagonists for several neurodegenerative diseases.. We examined whether repeated i.p. injections of ceftriaxone would, like glutamate antagonists, reduce the deficits in contralateral forepaw stepping produced by unilateral injections of 6-OHDA into the medial forebrain bundle of rats and reduce LID (as measured by abnormal involuntary movements).. In Experiment 1, daily injections of 100 mg/kg ceftriaxone improved contralateral forepaw stepping by 44%, and these therapeutic effects were still apparent 29 days following the cessation of treatment. In Experiment 2, daily injections of 50 mg/kg ceftriaxone were as effective as daily injections of 10 mg/kg L-DOPA in increasing contralateral forepaw stepping by 40%. These therapeutic effects of ceftriaxone were decreased by an injection of 10 mg/kg of the selective GLT-1 antagonist, dihydrokainate (DHK), and were still evident 69 days after the cessation of ceftriaxone injections. Furthermore, ceftriaxone did not produce dyskinesia by itself and reduced the development, but not the expression, of LID.. These data suggest that ceftriaxone, by producing a long-term increase in GLT-1 function and increasing the removal of synaptic glutamate, may offer several advantages over L-DOPA as therapy for PD.

Topics: Animals; Anti-Bacterial Agents; Antiparkinson Agents; Ceftriaxone; Central Nervous System Agents; Dyskinesia, Drug-Induced; Excitatory Amino Acid Transporter 2; Forelimb; Kainic Acid; Levodopa; Male; Medial Forebrain Bundle; Motor Activity; Oxidopamine; Parkinsonian Disorders; Rats, Long-Evans

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD) and treatment with drugs modulating glutamatergic activity may have beneficial effects. Ceftriaxone has been reported to increase glutamate uptake by increasing glutamate transporter expression. The aim of this study was to determine the effects of ceftriaxone on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Then, starting the next day (day 1), the rats were injected daily with either ceftriaxone (200 mg/kg/day, i.p.) or saline for 14 days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test. The treatment of ceftriaxone decreased the above MPTP-induced cognitive deficits. Furthermore, this study provides evidence that ceftriaxone inhibits MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area. In conclusion, these data support the idea that hyperactivity of the glutamatergic system is involved in the pathophysiology of PD and suggest that ceftriaxone may be a promising pharmacological tool for the development of new treatments for the dementia associated with PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Brain; CA1 Region, Hippocampal; Ceftriaxone; Cell Death; Cognition Disorders; Corpus Striatum; Male; Maze Learning; Memory, Short-Term; Microglia; Parkinsonian Disorders; Pars Compacta; Pyramidal Cells; Rats, Wistar; Recognition, Psychology

Parkinson's disease is caused by the degeneration of dopaminergic neurons in substantia nigra. There is no current promising treatment for neuroprotection of dopaminergic neurons. Ceftriaxone is a beta-lactam antibiotic and has been reported to offer neuroprotective effects (Rothstein, J.-D., Patel, S., Regan, M.-R., Haenggeli, C., Huang, Y.-H., Bergles, D.-E., Jin, L., Dykes, H.-M., Vidensky, S., Chung, D.-S., Toan, S.-V., Bruijn, L.-I., Su, Z.-Z., Gupta, P., and Fisher, P.-B. (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Nature433, 73-77). In the present study, efficacy of ceftriaxone in neuroprotection of dopaminergic neurons and amelioration of motor deficits in a rat model of Parkinson's disease were investigated. Ceftriaxone was administrated in 6-hydroxydopamine-lesioned rats. Using behavioral tests, grip strength and numbers of apomorphine-induced contralateral rotation were declined in the ceftriaxone-treated group. More importantly, cell death of dopaminergic neurons was found to decrease. In addition, both the protein expression and immunoreactivity for GLT-1 were up-regulated. The present results strongly indicate that ceftriaxone is a potential agent in the treatment of Parkinson's disease.

Topics: Animals; Behavior, Animal; Blotting, Western; Brain; Ceftriaxone; Dopaminergic Neurons; Female; Motor Activity; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley