Blocking the NAD+-Consuming Enzyme CD38 Protects Neurons and Eases Motor Deficits in a Rat Parkinson’s Model

Nicotinamide adenine dinucleotide, or NAD+, is an essential cofactor for a wide range of cellular processes, and its levels decline with age as biosynthesis slows and consumption accelerates. Researchers at Cerevance in Cambridge, United Kingdom, report in Frontiers in Pharmacology that pharmacologically blocking one of the main NAD+-consuming enzymes, CD38, raised NAD+ concentrations in the rodent brain, protected dopaminergic neurons from alpha-synuclein toxicity in cell culture, and reduced motor deficits in a rat model of Parkinson's disease. The rationale rests on where CD38 sits in brain biology.

Using NETSseq data from human post-mortem brain tissue, the team found that CD38 is enriched in astrocytes, the glial cells that support neuronal function. Because NAD+ depletion is thought to contribute to cellular dysfunction in age-related diseases of the central nervous system, an enzyme that actively degrades NAD+ in the brain represents an obvious point of intervention. The researchers developed and characterised CVN14, a small-molecule inhibitor designed to reach that target.

In assays against recombinant enzyme, CVN14 inhibited human CD38 with a half-maximal inhibitory concentration of 19.0 nanomolar, rat CD38 at 5.1 nanomolar and mouse CD38 at 2.4 nanomolar. Selectivity profiling showed the compound had no activity at CD157, the closest homologue of CD38, or at other NADases, addressing a key concern for any drug aimed at an enzyme family with shared chemistry. Two lines of evidence indicated that the compound does in the living brain what it is designed to do.

First, measurements in rats and mice showed that CVN14 treatment increased NAD+ levels in brain tissue, confirming that the molecule penetrates the central nervous system and engages its target in vivo. Second, the team ran a decisive control: in mice genetically engineered to lack CD38, CVN14 produced no further change in brain NAD+. That result indicates the drug's effect on NAD+ depends on the presence of its intended target and provides direct support for the compound's selectivity against other NAD+-consuming enzymes, rather than an off-target mechanism.

With target engagement established, the researchers tested whether CD38 inhibition could protect the neurons most affected by Parkinson's disease. In rat mesencephalic cultures, which contain the midbrain dopaminergic neurons that degenerate in patients, the team challenged the cells with alpha-synuclein, the protein whose misfolded aggregates define Parkinson's pathology. CVN14 treatment increased dopaminergic neuronal survival under this alpha-synuclein-induced toxicity.

The cultures also produced a second observation with potential mechanistic significance: treated cultures showed fewer neurons positive for pSer129 alpha-synuclein, the phosphorylated form of the protein widely used as a marker of pathological aggregates. The authors interpret this as support for further investigation into whether CD38 inhibition plays a role in the clearance of pathological protein, a possibility that would extend the drug's relevance beyond simply buffering cellular metabolism. The most translationally relevant experiment was conducted in live animals.

Rats received injections of AAV1/2 vectors carrying human alpha-synuclein, a widely used model in which expression of the human protein in the brain produces motor deficits resembling aspects of Parkinson's disease. In this model, CVN14 treatment reduced the motor deficits measured in the animals. Taken together with the in vitro neuroprotection and the pharmacodynamic data, the authors present the findings as preclinical support for CD38 inhibition as a therapeutic approach in Parkinson's disease.

The results come with the standard caveats of early-stage research. The cell-culture findings are in vitro observations, and the animal work was conducted in a single alpha-synuclein overexpression model in rats; neither establishes efficacy in humans. The authors note that genetic links between CD38 and Parkinson's disease provided part of the rationale for the study, but the present paper reports preclinical pharmacology and model data rather than clinical outcomes.

Whether raising brain NAD+ through CD38 inhibition produces meaningful benefit in patients, over what dosing regimen, and with what safety profile, remain questions for the clinical testing that would need to follow. Within those limits, the study delivers a coherent package: a selective, brain-penetrant inhibitor, demonstrated target engagement through a knockout control, neuroprotection against the disease-defining protein in vitro, and behavioural benefit in a rodent model of the disorder it aims to treat.

Subject of Research: CD38 inhibition as a preclinical therapeutic strategy for Parkinson's disease via NAD+ preservation and alpha-synuclein clearance

Article 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

Article References: Harvey, J. R. M., Wight, T. H., Roberts, M., Mulligan, V., Barker, D. F., Sherlock, C., Ossola, B., Hewer, R., Xu, X., Page, K., Powell, J., Bürli, R. W., Ramsden, N., Dawson, L. A., Carlton, M. B., Brice, N. L., & Stott, A. J. (2026). CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model. Frontiers in Pharmacology, 17, Article 1927552. https://doi.org/10.3389/fphar.2026.1927552

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1927552

Keywords: CD38, NAD+, Parkinson's disease, alpha-synuclein, CVN14, astrocytes, dopaminergic neurons, NADase inhibitor, rat model, preclinical research, neurodegeneration, drug discovery