{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusion: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Cerevance Ltd"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jenna R. M. Harvey"
    },
    {
      "affs": [
        0
      ],
      "name": "Thomas H. Wight"
    },
    {
      "affs": [
        0
      ],
      "name": "Maxine Roberts"
    },
    {
      "affs": [
        0
      ],
      "name": "Victoria Mulligan"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniel F. Barker"
    },
    {
      "affs": [
        0
      ],
      "name": "Chloe Sherlock"
    },
    {
      "affs": [
        0
      ],
      "name": "Bernardino Ossola"
    },
    {
      "affs": [
        0
      ],
      "name": "Richard Hewer"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiao Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Keith Page"
    },
    {
      "affs": [
        0
      ],
      "name": "Justin Powell"
    },
    {
      "affs": [
        0
      ],
      "name": "Roland W. Bürli"
    },
    {
      "affs": [
        0
      ],
      "name": "Nigel Ramsden"
    },
    {
      "affs": [
        0
      ],
      "name": "Lee A. Dawson"
    },
    {
      "affs": [
        0
      ],
      "name": "Mark B. Carlton"
    },
    {
      "affs": [
        0
      ],
      "name": "Nicola L. Brice"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrew J. Stott"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6gqv2z8q4vpkd.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1927552",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1927552/full",
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  "issns": [
    "1663-9812"
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  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RM1-950"
    ],
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
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  "openalex": "W7223311780",
  "pdf_url": "https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1927552/pdf",
  "pmcid": "PMC13739665",
  "pmid": "42996606",
  "published": "2026-10-23",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/6gqv2z8q4vpkd.ris",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Parkinson's Disease Mechanisms and Treatments",
      "subfield": "neurology"
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  ],
  "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",
  "title_text": "CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/6gqv2z8q4vpkd",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}