ABSTRACT
The standardized extract of Ginkgo biloba EGb 761 has been used to reduce cognitive dysfunction. The present study was designed to evaluate the effect of postischemic oral treatment with EGb 761 in a model of vascular dementia in gerbils. Daily oral posttreatment with EGb 761 led to a significant recovery of spatial memory assessed by the object location test, inhibited the decrease in plasma SOD activity and protected the hippocampal CA1 neurons, even when administered after the insult. These data provide further evidence for the therapeutic potential of EGb 761 in the treatment of vascular dementia.
Subject(s)
Dementia, Vascular/drug therapy , Ginkgo biloba , Hippocampus/drug effects , Memory Disorders/drug therapy , Neuroprotective Agents/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Animals , Brain Ischemia/blood , Brain Ischemia/complications , Brain Ischemia/drug therapy , Dementia, Vascular/blood , Dementia, Vascular/pathology , Disease Models, Animal , Gerbillinae , Hippocampus/pathology , Memory/drug effects , Memory Disorders/blood , Nerve Degeneration/blood , Nerve Degeneration/drug therapy , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Superoxide Dismutase/bloodABSTRACT
A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.
Subject(s)
Amantadine/therapeutic use , Antiparkinson Agents/therapeutic use , Disease Models, Animal , Dyskinesia, Drug-Induced/drug therapy , Parkinsonian Disorders/drug therapy , Purines/therapeutic use , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/toxicity , Amantadine/pharmacology , Amantadine/toxicity , Animals , Antiparkinson Agents/adverse effects , Antiparkinson Agents/pharmacology , Behavior, Animal , Benserazide/pharmacology , Biological Assay , Corpus Striatum , Dopamine/physiology , Dopamine Agents/pharmacology , Dopamine Agents/toxicity , Drug Administration Schedule , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Levodopa/adverse effects , Levodopa/pharmacology , Levodopa/toxicity , Male , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Placebos , Purines/pharmacology , Purines/toxicity , Random Allocation , Rats , Reproducibility of Results , Rotation , Sample Size , Single-Blind Method , Sympatholytics/toxicityABSTRACT
In this study, the effect of bilobalide, a purified terpene lactone component of the Ginkgo biloba extract (EGb 761), and EGb 761 against ischemic injury and against glutamate-induced excitotoxic neuronal death was compared. In the case of ischemic injury, neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in the hippocampal regions of gerbils was measured. A significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons at 7-days of reperfusion after 5 min of transient global forebrain ischemia. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before ischemia progressively protected hippocampal CA1 neurons against ischemia-induced neuronal death and reductions in COX III mRNA. In rat cerebellar neuronal cultures, addition of bilobalide or EGb 761 protected in a dose-dependent manner against glutamate-induced excitotoxic neuronal death [effective concentration (EC50) = 5 microg/ml (12 microM) forbilobalide and 100 microg/ml for EGb 761]. These results suggest thatboth EGb 761 and bilobalide protect against ischemia-induced neuronal death in vivo and glutamate-induced neuronal death in vitro by synergistic mechanisms involving anti-excitotoxicity, inhibition of free radical generation, scavenging of reactive oxygen species, and regulation of mitochondrial gene expression.