CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model
Year: 2026
Type: article
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.
Source: Frontiers in Pharmacology
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223311780