CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model
- 1Cerevance Ltd
Abstract
Introduction: Nicotinamide adenine dinucleotide (NAD ⁺ ), an essential cofactor for multiple cellular processes, is critical for cellular health. NAD ⁺ declines with age due to reduced biosynthesis and increased consumption. This causes cellular dysfunction, which exacerbates and contributes to the pathology of age-related CNS diseases, including Parkinson’s disease (PD). CD38 is an NAD ⁺ -consuming enzyme (NADase) that increases in expression with ageing and disease, likely contributing to the age-related decline in NAD ⁺ . Genetic links between CD38 and PD provide a rationale for exploring its function in disease.
Methods: NETSseq datasets from human post-mortem brain tissue were used to assess CD38 cell-type-specific expression. The pharmacological properties of CVN14, a brain-penetrant selective inhibitor previously described by our group, were characterised using in vitro CD38 enzyme assays, selectivity profiling, pharmacokinetic and brain penetration studies, and brain NAD ⁺ measurements in rats and mice. The effects of CD38 inhibition were evaluated in α-synuclein-challenged rat mesencephalic cultures and in a rat AAV1/2-hA53T α-synuclein model of PD.
Results: CD38 was highly enriched in astrocytes in the human brain. CVN14 potently inhibited recombinant human, rat, and mouse CD38, with IC ₅₀ values of 19.0, 5.1, and 2.4 nM, respectively. This compound was selective, having no activity at its closest homologue, CD157, or at other NADases. CVN14 increased brain NAD ⁺ in rats and mice with no effect in the CD38 knockout mouse, further demonstrating its selectivity against other NADases. In a rat mesencephalic culture, CVN14 showed evidence of increasing dopaminergic neuronal survival following α-synuclein-induced toxicity and of reducing the number of neurons positive for pSer129 α-synuclein, thus supporting further investigation into a potential role for CD38 inhibition in the clearance of pathological protein. In a rat AAV1/2-hA53T α-synuclein model of PD, CVN14 improved motor function in the cylinder test.
Conclusion: Our findings support further the investigation of CD38 inhibition as a therapeutic approach for PD. CVN14 elevated brain NAD ⁺ in rats and mice reduced motor deficits in a rat α-synuclein model of PD and was associated with increased neuronal survival and reduced pathological α-synuclein in vitro , highlighting the therapeutic potential of CD38 inhibition in PD and other α-synucleinopathies.
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BibTeX
@article{harvey2026cd38,
title = {{CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model}},
author = {Jenna R. M. Harvey and Thomas H. Wight and Maxine Roberts and Victoria Mulligan and Daniel F. Barker and Chloe Sherlock and Bernardino Ossola and Richard Hewer and Xiao Xu and Keith Page and Justin Powell and Roland W. Bürli and Nigel Ramsden and Lee A. Dawson and Mark B. Carlton and Nicola L. Brice and Andrew J. Stott},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1927552},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1927552/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model
AU - Jenna R. M. Harvey
AU - Thomas H. Wight
AU - Maxine Roberts
AU - Victoria Mulligan
AU - Daniel F. Barker
AU - Chloe Sherlock
AU - Bernardino Ossola
AU - Richard Hewer
AU - Xiao Xu
AU - Keith Page
AU - Justin Powell
AU - Roland W. Bürli
AU - Nigel Ramsden
AU - Lee A. Dawson
AU - Mark B. Carlton
AU - Nicola L. Brice
AU - Andrew J. Stott
PY - 2026
DA - 2026/10/23
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1927552
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1927552/full
AB - Introduction: Nicotinamide adenine dinucleotide (NAD ⁺ ), an essential cofactor for multiple cellular processes, is critical for cellular health. NAD ⁺ declines with age due to reduced biosynthesis and increased consumption. This causes cellular dysfunction, which exacerbates and contributes to the pathology of age-related CNS diseases, including Parkinson’s disease (PD). CD38 is an NAD ⁺ -consuming enzyme (NADase) that increases in expression with ageing and disease, likely contributing to the age-related decline in NAD ⁺ . Genetic links between CD38 and PD provide a rationale for exploring its function in disease. Methods: NETSseq datasets from human post-mortem brain tissue were used to assess CD38 cell-type-specific expression. The pharmacological properties of CVN14, a brain-penetrant selective inhibitor previously described by our group, were characterised using in vitro CD38 enzyme assays, selectivity profiling, pharmacokinetic and brain penetration studies, and brain NAD ⁺ measurements in rats and mice. The effects of CD38 inhibition were evaluated in α-synuclein-challenged rat mesencephalic cultures and in a rat AAV1/2-hA53T α-synuclein model of PD. Results: CD38 was highly enriched in astrocytes in the human brain. CVN14 potently inhibited recombinant human, rat, and mouse CD38, with IC ₅₀ values of 19.0, 5.1, and 2.4 nM, respectively. This compound was selective, having no activity at its closest homologue, CD157, or at other NADases. CVN14 increased brain NAD ⁺ in rats and mice with no effect in the CD38 knockout mouse, further demonstrating its selectivity against other NADases. In a rat mesencephalic culture, CVN14 showed evidence of increasing dopaminergic neuronal survival following α-synuclein-induced toxicity and of reducing the number of neurons positive for pSer129 α-synuclein, thus supporting further investigation into a potential role for CD38 inhibition in the clearance of pathological protein. In a rat AAV1/2-hA53T α-synuclein model of PD, CVN14 improved motor function in the cylinder test. Conclusion: Our findings support further the investigation of CD38 inhibition as a therapeutic approach for PD. CVN14 elevated brain NAD ⁺ in rats and mice reduced motor deficits in a rat α-synuclein model of PD and was associated with increased neuronal survival and reduced pathological α-synuclein in vitro , highlighting the therapeutic potential of CD38 inhibition in PD and other α-synucleinopathies.
SN - 1663-9812
ER -