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Backgroud: Erigeron floribundus is a herbaceous plant used in traditional Cameroonian medicine to treat diabetes mellitus. The aim of this study was to evaluate the antidiabetic properties of the aqueous extract of E. floribundus leaves (AEEF) in diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg) in normal rats fasted for 16 h. Subsequently, 30 diabetic male rats were divided into groups and treated orally for 21 days with distilled water (10 mL/kg), glibenclamide (3 mg/kg) and AEEF (300, 400, and 500 mg/kg). Body weight, food and water intake, blood glucose, insulin levels, lipid and oxidative profiles, as well as some markers of liver and kidney function were assessed. Histological sections of the rats' pancreas were taken. Results: AEEF and glibenclamide significantly increased (p

Activation of metabotropic glutamate 2 (mGlu2) receptors is a potential novel therapeutic approach for the treatment of parkinsonism. Thus, when administered as monotherapy or as adjunct to a low dose of L‐3,4‐dihydroxyphenylalanine (L‐DOPA), the mGlu2 positive allosteric modulator (PAM) LY‐487,379 alleviated parkinsonism in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned primates. Here, we sought to investigate the effect of biphenyl‐indanone A (BINA), a highly selective mGlu2 PAM whose chemical scaffold is unrelated to LY‐487,379, to determine if a structurally different mGlu2 PAM would also confer anti‐parkinsonian benefit. In monotherapy experiments, MPTP‐lesioned marmosets were injected with either vehicle, L‐DOPA/benserazide (15/3.75 mg/kg, positive control) or BINA (0.1, 1, 10 mg/kg). In adjunct to a low L‐DOPA dose experiments, MPTP‐lesioned marmosets were injected with L‐DOPA/benserazide (7.5/1.875 mg/kg) in combination with vehicle or BINA (0.1, 1, 10 mg/kg). Parkinsonism, dyskinesia and psychosis‐like behaviours (PLBs) were then quantified. When administered alone, BINA 1 and 10 mg/kg decreased parkinsonism severity by ~22% (p < 0.01) and ~47% (p < 0.001), when compared with vehicle, which was comparable with the global effect of a high L‐DOPA dose. When administered in combination with a low L‐DOPA dose, BINA 1 and 10 mg/kg decreased global parkinsonism by ~38% (p < 0.001) and ~53% (p < 0.001). BINA 10 mg/kg decreased global dyskinesia by ~94% (p < 0.01) and global PLBs by ~92% (p < 0.01). Our results provide additional evidence that mGlu2 positive allosteric modulation elicits anti‐parkinsonian effects. That this benefit is not related to a particular chemical scaffold suggests that it may be a class effect rather than the effect of a specific molecule. [ABSTRACT FROM AUTHOR]

We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR2) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR2/3) enhance the anti-parkinsonian action of l-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR2 positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR2 positive allosteric modulation and combined mGluR2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms. [ABSTRACT FROM AUTHOR]

There is mounting evidence that positive allosteric modulation of metabotropic glutamate type 2 receptors (mGluR2) is an efficacious approach to reduce the severity of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, psychosis-like behaviours (PLBs), while conferring additional anti-parkinsonian benefit. However, the mGluR2 positive allosteric modulators (PAMs) tested so far, LY-487,379 and CBiPES, share a similar chemical scaffold. Here, we sought to assess whether similar benefits would be conferred by a structurally-distinct mGluR2 PAM, biphenylindanone A (BINA). Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and PLBs were administered L-DOPA with either vehicle or BINA (0.1, 1, and 10 mg/kg) in a randomised within-subject design and recorded. Behaviour was analysed by a blinded rater who scored the severity of each of parkinsonism, dyskinesia and PLBs. When added to L-DOPA, BINA 0.1 mg/kg, 1 mg/kg, and 10 mg/kg all significantly reduced the severity of global dyskinesia, by 40%, 52% and 53%, (all P < 0.001) respectively. BINA similarly attenuated the severity of global PLBs by 35%, 48%, and 50%, (all P < 0.001) respectively. Meanwhile, BINA did not alter the effect of L-DOPA on parkinsonism exhibited by the marmosets. The results of this study provide incremental evidence of positive allosteric modulation of mGluR2 as an effective therapeutic strategy for alleviating dyskinesia and PLBs, without hindering the anti-parkinsonian action of L-DOPA. Furthermore, this therapeutic benefit does not appear to be confined to a particular chemical scaffold. [ABSTRACT FROM AUTHOR]

The availability of agonists and antagonists to modulate the activity of the 5- hydroxytryptamine (5-HT) type 3 ([5-HT.sub.3]) receptor has renewed interest in its role as a therapeutic target. Ondansetron is a highly selective [5-HT.sub.3] receptor antagonist that is well tolerated as an anti-emetic for patients undergoing chemotherapy. Preclinical studies in rat have shown the effects of small doses of ondansetron on cognition, behavioural sensitisation, and epilepsy. However, the pharmacokinetic (PK) profile of ondansetron in rat has not been described, which limits the translational relevance of these findings. Here, we aim to determine, in the rat, the PK profile of ondansetron in the plasma and to determine associated brain levels. The plasma PK profile was determined following acute subcutaneous administration of ondansetron (0.1,1, and 10 [micro]g/kg). Brain levels were measured following subcutaneous administration of ondansetron at 1 [micro]g/kg. Plasma and brain levels of ondansetron were determined using high-performance liquid chromatography --tandem mass spectrometry. Following administration of all three doses, measured ondansetron plasma levels ([approximately equal to] 30-3000 pg/mL) were below levels achieved with doses usually administered in the clinic, with a rapid absorption phase and a short half-life ([approximately equal to] 30-40 min). We also found that brain levels of ondansetron at 1 [micro]g/kg were significantly lower than plasma levels, with brain to plasma ratios of 0.45 and 0.46 in the motor and prefrontal cortices. We discuss our findings in the context of a minireview of the literature. We hope that our study will be helpful to the design of preclinical studies with therapeutic end-points. Key words: rat, ondansetron, pharmacokinetics, [5-HT.sub.3] receptor antagonist, HPLC-MS/MS. La disponibilite d'agonistes et d'antagonistes permettant de moduler l'activite des recepteurs de la 5-hydroxytryptamine (5-HT) de type 3 ([5-HT.sub.3]) a renouvele l'interet dans son role comme cible therapeutique. L'ondansetron est un antagoniste tres selectif des recepteurs [5-HT.sub.3] avec une bonne tolerabilite en tant qu'antiemetique chez les patients sous chimiotherapie. Des etudes precliniques chez le rat ont montre les effets de l'ondansetron a faibles doses sur l'etat cognitif, la sensibilisation comportementale et l'epilepsie. Cependant, le profil pharmacocinetique (PK) de l'ondansetron n'a pas ete decrit chez le rat, ce qui limite la pertinence translationnelle de ces resultats. Ici, nous cherchons a etablir le profil PK de l'ondansetron dans le plasma chez le rat et a etablir les niveaux cerebraux associes. Le profil PK plasmatique a ete etabli apres l'administration d'ondansetron (a 0,1,1 et 10 [micro]g/kg) par voie sous-cutanee. Nous avons mesure les niveaux cerebraux a la suite de l'administration sous-cutanee d'ondansetron a 1 [micro]g/kg. Nous avons etabli les niveaux plasmatiques et cerebraux d'ondansetron a l'aide de la chromatographie liquide a haute performance couple a la spectrometrie de masse en tandem. Apres l'administration de chacune des trois doses, nous avons mesure des niveaux plasmatiques d'ondansetron inferieurs a ceux obtenus avec des doses habituellement utilisees en clinique ([approximately equal to] 30-3000 pg/ mL), avec une phase d'absorption rapide et une courte demi-vie ([approximately equal to] 30-40 min). Nous avons aussi observe que les niveaux cerebraux d'ondansetron administre a 1 [micro]g/kg etaient nettement moins eleves que dans le plasma, avec des ratios cerveau a plasma de 0,45 et de 0,46 dans les cortex moteur et prefrontal, respectivement. Nous discutons de nos observations dans le contexte d'une courte synthese de la litterature. Nous esperons que notre etude sera utile pour la conception d'etudes precliniques avec des parametres d'evaluation therapeutiques. Mots-des: rat, ondansetron, pharmacocinetique, antagoniste des recepteurs [5- HT.sub.3], chromatographie liquide a haute performance en tandem avec la spectrometrie de masse., Introduction Initially described as the 'M receptor' in the guinea pig ileum, the 5-hydroxytryptamine (5-HT) type 3 ([5-HT.sub.3]) receptor is uniquely positioned in the 5-HT receptor family as the only [...]

Nelotanserin is a serotonin 2A and 2C (5‐HT2A/2C) inverse agonist that was previously tested in the clinic for rapid‐eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia has however not been investigated. As 5‐HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti‐dyskinetic potential of nelotanserin in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L‐DOPA to induce dyskinesia. On experimental days, they were administered L‐DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L‐DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti‐parkinsonian action of L‐DOPA. Our results highlight that nelotanserin may represent an efficacious anti‐dyskinetic drug and provide incremental evidence of the potential benefit of 5‐HT2A/2C antagonism/inverse agonism for drug‐induced dyskinesia in PD. [ABSTRACT FROM AUTHOR]

Rationale: Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). Objectives: We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia. Methods: Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured. Results: ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses. Conclusions: Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis. [ABSTRACT FROM AUTHOR]