{
  "abstract": "Background: Glaucoma is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell (RGC) loss, in which both intraocular pressure (IOP)-dependent and -independent mechanisms contribute to disease progression. Gabapentinoids target α2δ subunits of voltage-gated calcium channels (VGCCs), which regulate calcium-dependent processes relevant to both aqueous humor dynamics and retinal neuronal function. This systematic review evaluates heterogeneous evidence relevant to α2δ modulation of IOP regulation, retinal neuroprotection, and associated molecular and synaptic pathways. Methods: A systematic literature search was conducted across PubMed, Embase, Scopus, and Cochrane Library databases from inception. Studies investigating gabapentinoids or α2δ subunit modulation with outcomes related to IOP, RGC survival, or relevant molecular signaling were included. Risk of Bias (RoB) was assessed using the OHAT rating tool, and Certainty of Evidence (CoE) was rated on the GRADE four-level scale using initial confidence criteria from the OHAT approach. Due to heterogeneity in study design and outcomes, findings were synthesized narratively, with included studies divided and assessed separately within anterior segment pharmacology, anterior segment genetics, neuroprotection, and mechanistic bodies of evidence. Results: Of 1973 unique records screened, 11 studies met inclusion criteria, which were further subdivided into 15 experimental arms according to evidence type. Distinct evidence bodies were anterior segment pharmacology (5 study arms), anterior segment genetics (3 study arms), neuroprotection (4 study arms), and mechanistic (3 study arms). Across mouse and rabbit models of spontaneous ocular hypertension, topical pregabalin (PRG) consistently reduced IOP in a dose-dependent manner, with peak effects generally occurring 1.5–5 h after administration depending on strain and formulation. Plateaus in maximal IOP reduction were observed at 0.9% PRG solution in mice and 0.6–0.7% PRG microemulsion (ME) in rabbits. ME formulations of PRG consistently prolonged duration of action and increased cumulative exposure relative to non-ME PRG formulations. PRG ME achieved maximal IOP reduction comparable to that of 0.005% latanoprost solution while retaining their increased duration of action and cumulative exposure. Repeated once-daily PRG ME dosing maintained IOP-lowering responses over 21- and 60-day treatment periods. Genetic studies separately associated CACNA2D1/Cacna2d1 with IOP-related phenotypes and primary open-angle glaucoma susceptibility, providing target-level evidence. Preclinical posterior segment studies reported retinal structural preservation or improved RGC survival with PRG, while separate studies of GBP-L demonstrated RGC-survival effects associated with K-ATP channel activity rather than established α2δ modulation. Mechanistic studies separately identified thrombospondin-2 (TSP2)-α2δ1 signaling as a mediator of injury-associated synaptic remodeling, with pharmacologic disruption attenuating synaptic protein upregulation and improving axonal integrity. RoB varied across study arms and bodies of evidence. Anterior pharmacology included five Tier II study arms, anterior genetics included two Tier I arms and one Tier II arm, and all neuroprotection and mechanistic arms were Tier II. CoE was rated moderate for both anterior pharmacology and genetics, and low for both neuroprotection and mechanistic evidence. Conclusions: The available evidence is predominantly preclinical and heterogeneous. Moderate certainty within the defined anterior segment evidence body reflects consistency of the reported preclinical effect and does not establish clinical efficacy or independent reproducibility, as the topical PRG intervention literature is concentrated within a single investigative group. The neuroprotective and mechanistic findings remain hypothesis-generating and do not establish a unified mechanism or simultaneous IOP-lowering and neuroprotective action. Independent pharmacologic replication, validation in chronic glaucomatous neurodegeneration models, and long-term topical safety evaluation are prerequisites to discussions of clinical relevance.",
  "abstract_shown": true,
  "affiliations": [
    "College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA",
    "Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA",
    "Department of Computer Science and Software Engineering, Miami University, Oxford, OH 45056, USA",
    "Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Gideon Wall",
      "orcid": "0009-0000-8109-8350"
    },
    {
      "affs": [
        0
      ],
      "name": "Zirui Zhou",
      "orcid": "0009-0003-0480-1569"
    },
    {
      "affs": [
        1
      ],
      "name": "Benton Chuter",
      "orcid": "0000-0002-0354-0569"
    },
    {
      "affs": [
        0
      ],
      "name": "Caroline Owens"
    },
    {
      "affs": [
        2
      ],
      "name": "Noah Emmert",
      "orcid": "0009-0001-9370-9638"
    },
    {
      "affs": [
        1
      ],
      "name": "Mohammad Delsoz"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Mohamed Moustafa Ibrahim",
      "orcid": "0000-0001-7691-6128"
    },
    {
      "affs": [
        1
      ],
      "name": "Monica M. Jablonski",
      "orcid": "0000-0002-4021-3559"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bbz7d4wkdrp1h.bib",
  "cited_by": 0,
  "doi": "10.3390/jcm15218681",
  "fulltext_url": null,
  "id": "bbz7d4wkdrp1h",
  "issns": [
    "2077-0383"
  ],
  "landing_url": "https://www.mdpi.com/2077-0383/15/21/8681",
  "language": null,
  "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": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-06",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/bbz7d4wkdrp1h.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T00:21:41Z",
      "native_id": "10.3390/jcm15218681",
      "source": "crossref",
      "url": "https://www.mdpi.com/2077-0383/15/21/8681"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "journal-openalex:F27",
      "subfield": "general"
    }
  ],
  "title": "Pregabalin and α2δ Subunit Modulation: A Systematic Review of Preclinical Evidence for Intraocular Pressure Regulation and Retinal Neuroprotection",
  "title_text": "Pregabalin and α2δ Subunit Modulation: A Systematic Review of Preclinical Evidence for Intraocular Pressure Regulation and Retinal Neuroprotection",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T00:21:41Z",
  "url": "https://research.draconitic.com/paper/bbz7d4wkdrp1h",
  "venue": "Journal of Clinical Medicine",
  "versions": []
}