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

Adam G O'Mahony; Martina Mazzocchi; Alex Morris; Noelia Morales-Prieto; Caitriona Guinane; Sean L Wyatt; Louise M Collins; Aideen M Sullivan; Gerard W O'Keeffe

doi:10.1016/j.neuropharm.2025.110319

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. 2025 Jan 20:268:110319. doi: 10.1016/j.neuropharm.2025.110319. Online ahead of print.

Authors

Adam G O'Mahony¹, Martina Mazzocchi¹, Alex Morris², Noelia Morales-Prieto¹, Caitriona Guinane², Sean L Wyatt³, Louise M Collins⁴, Aideen M Sullivan⁵, Gerard W O'Keeffe⁶

Affiliations

¹ Department of Anatomy & Neuroscience, School of Medicine, University College Cork (UCC), Cork, Ireland.
² Department of Biological Sciences, Munster Technological University (MTU), Cork Campus, Cork, Ireland.
³ Cardiff School of Biosciences, Cardiff University, Wales, UK.
⁴ Department of Anatomy & Neuroscience, School of Medicine, University College Cork (UCC), Cork, Ireland; Department of Physiology, School of Medicine, UCC, Cork, Ireland.
⁵ Department of Pharmacology and Therapeutics, School of Medicine, UCC, Cork, Ireland; APC Microbiome Ireland, UCC, Cork, Ireland. Electronic address: a.sullivan@ucc.ie.
⁶ Department of Anatomy & Neuroscience, School of Medicine, University College Cork (UCC), Cork, Ireland; APC Microbiome Ireland, UCC, Cork, Ireland. Electronic address: g.okeeffe@ucc.ie.

PMID: 39842624
DOI: 10.1016/j.neuropharm.2025.110319

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.

Keywords: 6-Hydroxydopamine; HDAC; Histone deacetylase; Histone deacetylase inhibitor; Neuroprotection; Parkinson's disease; TMP269.