Small molecule TrkB agonist deoxygedunin protects nigrostriatal dopaminergic neurons from 6-OHDA and MPTP induced neurotoxicity in rodents.

Dopaminergic neurons loss in the substantia nigra (SN) and dopamine (DA) content loss in the striatum correlate well with disease severity in Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family and is necessary for the survival and development of DA neurons in the SN. Deficits in BDNF/TrkB receptors signaling contribute to the dysfunction of PD. Deoxygedunin, a derivative of gedunin produced from Indian neem tree, binds TrkB receptor and activates TrkB and its downstream signaling cascades in a BDNF-independent manner, and possesses neuroprotective effects in vitro and in vivo. In this study, we tested the neuroprotective effects of deoxygedunin in 6-hydroxydopamine (6-OHDA)-lesioned rat model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease. Rats were treated with deoxygedunin 5 mg/kg (i.p.) for one month started two weeks before 6-OHDA lesion (pre-treatment), or for two weeks right after lesion (post-treatment), with isovolumetric vehicle as control and normal. Mice were given deoxygedunin 5 mg/kg (i.p.) for 2 weeks and administrated with MPTP twice at the dose of 20 mg/kg (i.p.) on day 7. The results revealed that pretreatment with deoxygedunin improved PD models' behavioral performance and reduced dopaminergic neurons loss in SN, associated with the activation of TrkB receptors and its two major signaling cascades involving mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). Thus, our current study indicates that deoxygedunin, as a small molecule TrkB agonist, displays prominent neuroprotective properties, providing a novel therapeutic strategy for treating Parkinson's disease.

Nie S ，Xu Y ，Chen G ，Ma K ，Han C ，Guo Z ，Zhang Z ，Ye K ，Cao X ... -  《-》

7,8-dihydroxyflavone protects 6-OHDA and MPTP induced dopaminergic neurons degeneration through activation of TrkB in rodents.

Brain-derived neurotrophic factor (BDNF) is a notably important neurotrophin which regulates neuronal survival and differentiation in the nervous system. However, its clinical usage is particularly limited. 7,8-dihydroxyflavone (7,8-DHF), which acts as a selective agonist of BDNF receptor TrkB, is reported to possess neuroprotective effects both in vitro and in vivo. Here we explored the potent neuroprotective effects of 7,8-DHF in 6-OHDA induced rat and MPTP induced mouse model of Parkinsonism. The results demonstrated that treatment with 7,8-DHF in drinking water for four weeks (two weeks before 6-OHDA+two weeks after 6-OHDA lesion) significantly improved dopamine-mediated behaviors in 6-OHDA rat model, and prevented the loss of dopaminergic neurons in the substantia nigra (SN). Phospho-Y816-TrkB immunostaining showed that TrkB phosphorylation was significantly elevated in the SN in 7,8-DHF pretreated group, indicating 7,8-DHF activated TrkB and likely contributed to its neuroprotective effects. 7,8-DHF also protected acute MPTP neurotoxicity in mice but did not affect the climbing behavior in pole test. Thus our study indicates the neuroprotective properties of 7,8-DHF through the activation of TrkB, which provides a novel therapeutic treatment for Parkinson's disease.

Luo D ，Shi Y ，Wang J ，Lin Q ，Sun Y ，Ye K ，Yan Q ，Zhang H ... -  《-》

Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats.

Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3 mg/kg) was administered intraperitoneally at 24 h and 30 min prior to the creation of an intranigral 6-OHDA lesion. A reduction in TH protein expression began at 3 days and a prominent decrease was observed at 7 days post-lesion, and decreases of dopamine (DA) levels began at 1 day post-lesion. In contrast, GFAP expression was significantly increased at 3 days and preserved for up to 7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6h post-lesion while that of the caudal striatum was increased at 12 h. In the 6-OHDA-lesioned model, the activation of PPARγ by rosiglitazone significantly prevented TH protein expression reductions, and inhibited 6-OHDA-induced microglia activation in striatum. In addition, rosiglitazone attenuated in production of both COX-2 and TNF-α expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection observed with rosiglitazone treatment may be partially due to the attenuation of COX-2 production and the strengthening of astrocyte function. Our results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages.

Lee EY ，Lee JE ，Park JH ，Shin IC ，Koh HC ... -  《-》

A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease.

The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. GLP-1 analogues are currently on the market as treatments for type II diabetes. We previously showed that the novel dual agonist (DA-JC1) was effective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here we demonstrate that DA-JC1 is neuroprotective in the 6-OHDA brain lesion rat model of PD. When treating rats for 6 weeks with DA-JC1 at 25 nmol/kg ip once-daily, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. The number of TH positive dopaminergic neurons in the substantia nigra was decreased by 6-OHDA lesion and was increased by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. In western blot analysis, levels of the growth factor GDNF and pAkt/CREB cell signaling was enhanced by DA-JC1. The autophagy marker Beclin1 was also activated by the drug. The results demonstrate that dual GLP-1/GIP receptor agonists show promise as a novel treatment for PD.

Jalewa J ，Sharma MK ，Gengler S ，Hölscher C ... -  《-》

The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson's disease.

Liu H ，Jia L ，Chen X ，Shi L ，Xie J ... -  《-》