PT109B, a Multikinase Inhibitor, Converts Astrocytes into Dopaminergic Neurons and Alleviates Parkinson's Disease in Mice DOI

Cailv Wei,

Yang Yang, Tsz Hei Fong

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Abstract Background Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons (DANs), leading to motor dysfunction, while current treatments fail restore neuronal loss. Reprogramming astrocytes into induced DANs small molecules offers a promising therapeutic strategy, but existing methods face challenges including low efficiency and complex mechanisms. PT109B, novel multi-kinase inhibitor, has demonstrated neurogenic synaptogenic potential in neural progenitor cells, as well glioblastoma differentiation capacity, yet its ability directly convert functional effects PD remain unclear. Methods Primary rat midbrain were treated with 10 µM PT109B evaluate reprogramming via immunofluorescence (GFAP, MAP2, NeuN, TH, DAT) electrophysiological recordings. RNA sequencing was performed at 1.5, 3, 6 hours post-treatment assess transcriptional changes. In vivo, (100 mg/kg) administered orally for 12 weeks 6-OHDA-induced mice, labeled AAV5-GFAP-EGFP. Behavioral tests (apomorphine rotation, pole test, rotarod, open field), retrograde tracing, immunohistochemistry conducted effects. Results initiated astrocyte-to-neuron conversion early 3 hours, yielding 20% TH⁺ 2 vitro, mature properties action potentials, sodium currents sustained dopamine release (> months). Mechanistically, drove this through cell cycle arrest, astrocytic activation, upregulation key basic Helix-Loop-Helix (b-HLH) transcription factors (NeuroD1, Ascl1, Ngn2). In vivo, oral administration mouse model exhibited significant efficacy striatum, improved functions. Conclusions efficiently converts rapid ameliorates PD-related pathology deficits, presenting safe effective single-molecule strategy PD.

Language: Английский

PT109B, a Multikinase Inhibitor, Converts Astrocytes into Dopaminergic Neurons and Alleviates Parkinson's Disease in Mice DOI

Cailv Wei,

Yang Yang, Tsz Hei Fong

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Abstract Background Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons (DANs), leading to motor dysfunction, while current treatments fail restore neuronal loss. Reprogramming astrocytes into induced DANs small molecules offers a promising therapeutic strategy, but existing methods face challenges including low efficiency and complex mechanisms. PT109B, novel multi-kinase inhibitor, has demonstrated neurogenic synaptogenic potential in neural progenitor cells, as well glioblastoma differentiation capacity, yet its ability directly convert functional effects PD remain unclear. Methods Primary rat midbrain were treated with 10 µM PT109B evaluate reprogramming via immunofluorescence (GFAP, MAP2, NeuN, TH, DAT) electrophysiological recordings. RNA sequencing was performed at 1.5, 3, 6 hours post-treatment assess transcriptional changes. In vivo, (100 mg/kg) administered orally for 12 weeks 6-OHDA-induced mice, labeled AAV5-GFAP-EGFP. Behavioral tests (apomorphine rotation, pole test, rotarod, open field), retrograde tracing, immunohistochemistry conducted effects. Results initiated astrocyte-to-neuron conversion early 3 hours, yielding 20% TH⁺ 2 vitro, mature properties action potentials, sodium currents sustained dopamine release (> months). Mechanistically, drove this through cell cycle arrest, astrocytic activation, upregulation key basic Helix-Loop-Helix (b-HLH) transcription factors (NeuroD1, Ascl1, Ngn2). In vivo, oral administration mouse model exhibited significant efficacy striatum, improved functions. Conclusions efficiently converts rapid ameliorates PD-related pathology deficits, presenting safe effective single-molecule strategy PD.

Language: Английский

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