Investigation of the antidyskinetic site of action of metabotropic and ionotropic glutamate receptor antagonists. Intracerebral infusions in 6-hydroxydopamine-lesioned rats with levodopa-induced dyskinesia.

Long-term levodopa replacement therapy in Parkinson's disease is confounded by abnormal involuntary movements, known as levodopa induced dyskinesia (LID). Dysfunctional glutamatergic neurotransmission has been implicated in the pathogenesis of LID making metabotropic and ionotropic glutamate receptors attractive novel therapeutic targets. The objective of the present study was to investigate the antidyskinetic site of action of different glutamate receptor antagonists in the brain. For that purpose, metabotropic glutamate subtype 5 (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride, MTEP), NMDA NR2B selective ((aR,bS)-a-(4-Hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate, Ro 25-6981) and AMPA (2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, NBQX) receptor antagonists or saline were administered by intracerebral infusion in the caudate-putamen (CPu), the substantia nigra zona reticulata (SNr) or the subthalamic nucleus (STN) of 6-hydroxydopamine-lesioned rats exhibiting LID. Dyskinesia was assessed with the modified version of the rat Abnormal Involuntary Movements scale (AIMS). Ro 25-6981 and to a lesser extent NBQX improved dyskinesia (82% and 19% reduction in AIM score respectively) after infusion in the caudate-putamen. None of the three drugs managed to noticeably reduce AIM score after infusion in the SNr. MTEP was the only drug that produced a reduction in AIM score (48%) when infused in STN. In conclusion, while the striatum proved important in the antidyskinetic action of NMDA and AMPA receptor antagonists, the results of this study highlight also the importance of the metabotropic glutamate receptors that reside in the STN as therapeutic targets in the treatment of LID.

Gender association of the angiotensin-converting enzyme gene with ischaemic stroke.

We examined the association of the NG011648 polymorphism (insertion/deletion) of the angiotensin-converting enzyme (ACE) gene with ischaemic stroke occurrence, subtype of ischaemic stroke and ischaemic stroke patients' gender. Patients with first ever ischaemic stroke were recruited prospectively in a period of 18 months. Controls were matched with the patients for age, gender, and known risk factors for stroke. Demographic data, medical history, and vascular risk factors were collected. Genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme analysis. Stroke and control groups were compared in regard to the prevalence of the NG011648 polymorphism. One hundred and seventy-six patients with ischaemic stroke and 178 controls were recruited and genotyped for NG011648 polymorphism (I/D) of the ACE gene. No significant difference in allele and genotype distributions emerged between control and patient groups, nor in the two subtype groups of lacunars and large artery atherosclerosis. After the data were stratified by gender, a low incidence of II homozygosity in female patients versus female controls (p = 0.05) and male patients (p = 0.013, Z score: -2.49) was found. Our results indicate that I/D polymorphisms may have a role in stroke onset, in respect to gender, with a possible favourable effect of II genotype in females.