Neuroprotective efficacy of the glucocorticoid receptor modulator PT150 in the rotenone mouse model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.

Latham AS ，Rocha SM ，McDermott CP ，Reigan P ，Slayden RA ，Tjalkens RB ... -  《-》

Neuroprotective Efficacy of the Glucocorticoid Receptor Modulator PT150 in the Rotenone Mouse Model of Parkinson's Disease.

Latham AS ，Rocha SM ，McDermott CP ，Reigan P ，Slayden RA ，Tjalkens RB ... -  《-》

Rotenone induces regionally distinct α-synuclein protein aggregation and activation of glia prior to loss of dopaminergic neurons in C57Bl/6 mice.

Rotenone is a naturally occurring insecticide that inhibits mitochondrial complex I and leads to neurochemical and neuropathological deficits closely resembling those in Parkinson's disease (PD). Deficits include loss of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), decreased dopamine levels and aggregation of misfolded alpha-synuclein (p129). In rat models of rotenone-induced parkinsonism, the progression of neuronal injury has been associated with activation of microglia and astrocytes. However, these neuroinflammatory changes have been challenging to study in mice, in part because the systemic rotenone exposure model utilized in rats is more toxic to mice. To establish a reproducible murine model of rotenone-induced PD, we therefore investigated the progression of neuroinflammation, protein aggregation and DAn loss in C57Bl/6 mice by exposing animals to 2.5 mg/kg/day rotenone for 14 days, followed by a two-week period where neuroinflammation is allowed to progress. Our results indicate that initial cellular dysfunction leads to increased formation of proteinase K-resistant p129 aggregates in the caudate-putamen and SNpc. Clearance of these aggregates was region- and cell type-specific, with the early appearance of reactive astrocytes coinciding with accumulation of p129 in the SNpc. Phagocytic microglial cells containing p129 aggregates were observed proximal to p129+ DAn in the SNpc. The majority of neuronal loss in the SNpc occurred during the two-week period after rotenone exposure, subsequent to the peak of microglia and astrocyte activation, as well as the peak of p129 aggregation. A secondary peak of p129 coincided with neurodegeneration at later timepoints. These data indicate that systemic exposure to rotenone in C57Bl/6 mice causes progressive accumulation and regional spread of p129 aggregates that precede maximal loss of DAn. Thus, activation of glial cells and aggregation of p129 appear to drive neuronal loss following neurotoxic stress imposed by exposure to rotenone.

Rocha SM ，Bantle CM ，Aboellail T ，Chatterjee D ，Smeyne RJ ，Tjalkens RB ... -  《-》

Neuroprotective effect of a standardized extract of Centella asiatica ECa233 in rotenone-induced parkinsonism rats.

Mitochondrial dysfunction and reactive oxygen species (ROS) generation cause dopaminergic neurodegeneration in Parkinson's disease. The neuroprotective approach is a promising strategy to slow disease progression in Parkinson's disease. A standardized extract of Centella asiatica ECa233 has been previously reported to have pharmacological effects in the central nervous system. This study aimed to determine the neuroprotective effect and mechanisms of ECa233 in rotenone-induced parkinsonism rats. Rats were orally given either vehicle or ECa233 (10, 30 and 100 mg/kg) for 20 consecutive days. Rotenone (2.5 mg/kg i.p.) was given to parkinsonism (PD) and ECa-treated rats from day 15 to 20. Locomotor activity was recorded on day 1, 14, 17 and 20. Tyrosine-hydroxylase (TH) immunohistological staining was used to determine dopaminergic neurons in the substantia nigra and striatum. Furthermore, mitochondrial complex I activity, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase protein expression were measured in brain tissue. Rats receiving ECa233 30 mg/kg showed a significant increase in distances (p < 0.01) together with a higher number and intensity of dopaminergic neurons in the substantia nigra and striatum (p < 0.001) compared to PD rats. ECa233 (30 mg/kg) protected against mitochondrial complex I inhibition, decreased MDA levels (p < 0.05) and increased SOD (p < 0.01) and catalase (p < 0.05) expression. ECa233 can protect against rotenone-induced motor deficits and dopaminergic neuronal death. These effects are mediated through the protection of mitochondrial complex I activity, the effects of antioxidants and the enhancement of antioxidant enzyme expression.

Teerapattarakan N ，Benya-Aphikul H ，Tansawat R ，Wanakhachornkrai O ，Tantisira MH ，Rodsiri R ... -  《-》

Gintonin Mitigates MPTP-Induced Loss of Nigrostriatal Dopaminergic Neurons and Accumulation of α-Synuclein via the Nrf2/HO-1 Pathway.

Jo MG ，Ikram M ，Jo MH ，Yoo L ，Chung KC ，Nah SY ，Hwang H ，Rhim H ，Kim MO ... -  《-》