Neuroprotection and Functional Recovery Associated with Decreased Microglial Activation Following Selective Activation of mGluR2/3 Receptors in a Rodent Model of Parkinson's Disease.

Clinical trials have demonstrated positive proof of efficacy of dual metabotropic glutamate receptor 2/3 (mGluR2/3) agonists in both anxiety and schizophrenia. Importantly, evidence suggests that these drugs may also be neuroprotective against glutamate excitotoxicity, implicated in the pathogenesis of Parkinson's disease (PD). However, whether this neuroprotection also translates into functional recovery is unclear. In the current study, we examined the neuroprotective efficacy of the dual mGluR2/3 agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), and whether this is accompanied by behavioral recovery in a rodent 6-hydroxydopamine (6-OHDA) model of PD. We now report that delayed post lesion treatment with 2R,4R-APDC (10 nmol), results in robust neuroprotection of the nigrostriatal system, which translated into functional recovery as measured by improved forelimb use asymmetry and reduced (+)-amphetamine-induced rotation compared to vehicle treated animals. Interestingly, these beneficial effects were associated with a decrease in microglial markers in the SNc, which may suggest an antiinflammatory action of this drug.

Short-term supplementation with plant extracts rich in flavonoids protect nigrostriatal dopaminergic neurons in a rat model of Parkinson's disease.

OBJECTIVE: Antioxidants from plants were known to reduce the oxidative stress by scavenging free radicals, chelating metal ions and reducing inflammation. As increased oxidative stress was implicated in the nigrostriatal dopaminergic neuronal loss in Parkinson's disease (PD), we have assessed whether the plant extracts protects the nigrostriatal dopaminergic neurons in the animal model of PD. METHODS: Male adult Sprague-Dawley rats were treated orally between 10 am-11 am each day with the extracts from tangerine peel, grape seeds, cocoa and red clover for four days. One hour after the final dosing, the left medial forebrain bundle was lesioned by infusing the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA; 12 microg) under anaesthesia. Seven days post-lesion, the number of dopaminergic cells in the substantia nigra pars compacta and the levels of dopamine and its metabolites 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striata were quantified and compared with the vehicle-treated groups. RESULTS: Compared to the unlesioned side, 6-OHDA lesions significantly reduced the number of dopaminergic cells and the levels of dopamine and its metabolites DOPAC and HVA in the vehicle-treated animals. Pretreatment of animals with extracts of tangerine peel (rich in polymethoxylated flavones; 35 mg/kg/day), cocoa-2 (rich in procyanidins; 100 mg/kg/day) and red clover (rich in isoflavones; 200 mg/kg/day) significantly attenuated the 6-OHDA-induced dopaminergic loss. However, no significant protection was seen in animals supplemented with red and white grape seeds (rich in catechins; 100 mg/kg/day), and cocoa-1 (rich in catechins; 100 mg/kg/day). CONCLUSIONS: Pre-treatment of plant extracts rich in polymethoxylated flavones, procyanidins and isoflavones but not catechins protected the nigrostriatal dopaminergic neurons in the rat model of PD.

Subtype selective antagonism of substantia nigra pars compacta Group I metabotropic glutamate receptors protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo.

Evidence suggests that increased glutamatergic input to the substantia nigra pars compacta as a result of hyperactivity of subthalalmic nucleus output pathways may contribute to the progressive degeneration of nigral dopaminergic neurones in Parkinson's disease (PD), a debilitating neurodegenerative disorder which affects approximately 1% of people aged over 65. Substantial electrophysiological evidence suggests that the excitation of nigral dopaminergic neurones is regulated by the activation of Group I metabotropic glutamate receptors (mGluR), comprising mGluR1 and mGluR5 subtypes. As activation of these receptors by endogenous glutamate may promote multiple cascades leading to excitotoxic neuronal death, it may be hypothesised that functional antagonism of Group I mGluR should be neuroprotective and could form the basis of a novel neuroprotective treatment for PD. To investigate this hypothesis, the neuroprotective potential of the selective competitive mGlu1 antagonist (+)-2-methyl-4-carboxyphenylglycine ((S)-(+)-alpha-amino-4-carboxy-2-methlybenzeneacetic acid; LY367385) and the selective allosteric mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was tested in a rodent 6-hydroxydopamine (6-OHDA) model of PD in vivo. Both acute and subchronic intranigral administration of either LY367385 or MPEP resulted in significant neuroprotection of nigral tyrosine hydroxylase immunoreactive cell bodies, which correlated closely with prevention of striatal monoamine depletion following 6-OHDA lesioning. This neuroprotective action of LY367385 and MPEP displayed a clear concentration-dependent effect, suggesting a receptor-mediated mechanism of action. LY367385 produced robust neuroprotection at all concentrations tested (40, 200 and 1000 nmol in 4 microL), whilst MPEP displayed a bell-shaped neuroprotective profile with significant neuroprotection at low concentrations (2 and 10 nmol in 4 microL) but not at higher concentrations (50 nmol). Importantly, subchronic intranigral administration of MPEP and LY367385 appeared to slow the degeneration of remaining nigral dopaminergic neurones and prevented further striatal dopamine depletion in animals with established 6-OHDA induced nigrostriatal lesions, suggesting that these compounds may significantly influence disease progression in this model.

Selective activation of group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutryic acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo.

Evidence from several studies suggests that the progressive degeneration of dopaminergic (DA) neurones of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) may in part be due to excessive release of glutamate from subthalamic projections onto nigral DA neurones. Previous in vitro studies have demonstrated that selective activation of Group III metabotropic glutamate receptors (mGluR) negatively modulates excitatory transmission in the SNc and is neuroprotective against glutamate-mediated toxicity. Consistent with this, we have reported preliminary data indicating that the selective group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) can also protect the nigrostriatal system against 6-hydroxydopamine (6-OHDA) toxicity in vivo. We have now extended these preliminary studies in this model and report here that both acute and subchronic intranigral injections of l-AP4 provide significant protection of the nigrostriatal system against 6-OHDA toxicity. This neuroprotection displays a bell-shaped profile with a clear concentration-dependent relationship. In contrast, when administered to animals 7 days post-6-OHDA lesioning, l-AP4 significantly protects the functionality but not the integrity of the nigrostriatal system. We further demonstrate that neuroprotection by l-AP4 in vivo is reversed by coadministration of the selective Group III mGluR antagonist (RS)-alpha-methylserine-O-phosphate, confirming a receptor-mediated mechanism of action. These data provide further compelling evidence that selective activation of Group III mGluR is neuroprotective in an in vivo experimental model of PD, a finding that may have important implications for the future treatment of this disease.

Assessment of the polyphenolic composition of the organic extracts of Mauritian black teas: a potential contributor to their antioxidant functions.

There is increasing interest in the emerging view that tea improves the antioxidant status in vivo and thereby helps to lower risk of certain types of cancer, coronary heart disease and stroke and its component biofactors could provide prophylactic potential for these diseases. The polyphenolic composition and the antioxidant properties of organic extracts (acetone/methanol) of Mauritian commercial black teas were evaluated. HPLC data of the individual compounds revealed remarkably high levels (+)-Catechin ((+)-C), (-)-epicatechin ((-)-EC), (-)-epicatechin 3-gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (-)-epigallocatechin 3-gallate ((-)-EGCG) and gallic acid. Analysis of hydrolysed extracts indicated that quercetin was the dominant flavonol aglycone with traces of myricetin and kaempferol. Based on the Ferric Reducing Antioxidant Power (FRAP) and the Trolox Equivalent Antioxidant Capacity (TEAC) assays Extra tea from Bois Chéri exhibited the highest antioxidant potential. Linear regression analyses showed that the antioxidant capacities of the organic extracts are strongly influenced by total phenols (TEAC: r=0.95 and FRAP: r=0.96) and to a lesser extent by total proanthocyanidin and total flavonoid contents. Catechins and gallic acid seem to add up to the overall antioxidant capacity of black tea extracts. The fresh tea leaves had high levels of total phenols, total flavonoids, total proanthocyanidin and exhibited greater antioxidant potential when compared with black teas. Organic extracts of endemic teas represent useful source of phenolic antioxidants supplements for prophylactic use.

Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease.

Although the cause of dopaminergic cell death in Parkinson's disease (PD) remains unknown, oxidative stress has been strongly implicated. Because of their ability to combat oxidative stress, diet derived phenolic compounds continue to be considered as potential agents for long-term use in PD. This study was aimed at investigating whether the natural phenolic compounds curcumin, naringenin, quercetin, fisetin can be neuroprotective in the 6-OHDA model of PD. Unilateral infusion of 6-OHDA into the medial forebrain bundle produced a significant loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) as well as a decreased of dopamine (DA) content in the striata in the vehicle-treated animals. Rats pretreated with curcumin or naringenin showed a clear protection of the number of TH-positive cells in the SN and DA levels in the striata. However, neither pretreatment with quercetin nor fisetin had any effects on TH-positive cells or DA levels. The ability of curcumin and naringenin to exhibit neuroprotection in the 6-OHDA model of PD may be related to their antioxidant capabilities and their capability to penetrate into the brain.

Differences in dopaminergic neuroprotective effects of estrogen during estrous cycle.

Previous studies suggest that estrogen treatment protects nigrostriatal dopaminergic neurons, but have not examined whether the changes in estrogen levels during estrous cycle can influence the susceptibility of these neurons to neurotoxins. Here we show that the loss of dopaminergic neurons in the substantia nigra was greater in animals lesioned at diestrus (low estrogen) using 6-hydroxydopamine or buffered iron chloride, when compared with animals lesioned at proestrus (high estrogen). Lesioning at diestrus with 6-hydroxydopamine reduced the striatal dopamine content, whereas the dopamine content was preserved in animals lesioned at proestrus. The density of the dopamine transporter, upon which 6-hydroxydopamine toxicity is dependent, was lower when circulating estrogen was high. These results thus support a neuroprotectory role for estrogen.