O'Mahony, Adam G., Mazzocchi, Martina, Morris, Alex, Morales-Prieto, Noelia, Guinane, Caitriona, Wyatt, Sean L.  ORCID: https://orcid.org/0000-0002-0572-234X, Collins, Louise M., Sullivan, Aideen M. and O'Keeffe, Gerard W.
2025.
The class-IIa HDAC inhibitor TMP269 promotes BMP-Smad signalling and is neuroprotective in in vitro and in vivo 6-hydroxydopamine models of Parkinson's disease.
Neuropharmacology
268
, 110319.
10.1016/j.neuropharm.2025.110319
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Abstract
Degeneration of midbrain nigrostriatal dopaminergic neurons is a pathological hallmark of Parkinson's disease (PD). Peripheral delivery of a compound(s) to arrest or slow this dopaminergic degeneration is a key therapeutic goal. Pan-inhibitors of histone deacetylase (HDAC) enzymes, key epigenetic regulators, have shown therapeutic promise in PD models. However as there are several classes of HDACs (ClassI-IV), class-specific inhibition will be important to ensure target specificity. Here we examine the neuroprotective potential of the Class-IIa HDAC inhibitor, TMP269. We show that TMP269 protected against 6-hydroxydopamine (6-OHDA)-induced neurite injury in SH-SY5Y cells and cultured rat ventral mesencephalic dopaminergic neurons. We find that TMP269 upregulated the neurotrophic factor BMP2 and BMP-Smad dependent transcription signalling in SH-SY5Y cells, which was necessary for its neuroprotective effect against 6-OHDA-induced injury. Furthermore, peripheral continuous infusion of 0.5 mg/kg of TMP269 for 7 days via a mini-osmotic pump, reduced forelimb impairments induced by striatal 6-OHDA administration. TMP269 also protected dopaminergic neurons in the substantia nigra and their striatal terminals from striatal 6-OHDA-induced neurodegeneration and prevented the 6-OHDA-induced increases in the numbers of IBA1-positive microglia in the striatum and substantia nigra in vivo. TMP269 also prevented 6-OHDA-induced decreases in BMP2, pSmad1/5 and acetylated histone 3 levels, and it reversed 6-OHDA-induced increase in nuclear HDAC5 in dopaminergic neurons in the substantia nigra. These data add to the growing body of evidence that Class-IIa specific HDAC inhibitors may be pharmacological agents of interest for peripheral delivery with the goal of neuroprotection in PD.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Biosciences |
| Publisher: | Elsevier |
| ISSN: | 0028-3908 |
| Date of First Compliant Deposit: | 30 January 2025 |
| Date of Acceptance: | 18 January 2025 |
| Last Modified: | 12 Feb 2025 11:45 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/175755 |
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