{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:48:12Z","timestamp":1792180092825,"version":"4.4.0"},"reference-count":215,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"crossref","award":["#25-75-10137"],"award-info":[{"award-number":["#25-75-10137"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"crossref"}]},{"award":["#25-75-10137"],"award-info":[{"award-number":["#25-75-10137"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood\u2013brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries\u2014including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury\u2014as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases\u2014including Alzheimer\u2019s disease, Parkinson\u2019s disease, and amyotrophic lateral sclerosis\u2014Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32\/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial\u2013neuronal communication and cognitive\u2013emotional dysfunction. In epilepsy, increased Cx43\/Cx30 expression contributes to neuronal hypersynchronization and blood\u2013brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx\u2014particularly Cx43\u2014occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation.<\/jats:p>","DOI":"10.3390\/molecules31081341","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T07:15:08Z","timestamp":1776669308000},"page":"1341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Dual Role of Connexins in Stroke, Neurotrauma, Neurodegenerative and Psychiatric Disorders: A Global Systematic Review"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4036-5410","authenticated-orcid":false,"given":"Stanislav","family":"Rodkin","sequence":"first","affiliation":[{"name":"Research Laboratory \u201cMedical Digital Images Based on the Basic Model\u201d, Department of Bioengineering, Institute of Living Systems, Don State Technical University, 344000 Rostov-on-Don, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-0404","authenticated-orcid":false,"given":"Mitkhat","family":"Gasanov","sequence":"additional","affiliation":[{"name":"Hospital Therapy Department, Medical Institute, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2816-3541","authenticated-orcid":false,"given":"Alexander","family":"Tushev","sequence":"additional","affiliation":[{"name":"Neurology and Neurosurgery Department, Rostov State Medical University, 344022 Rostov-on-Don, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Belousova","sequence":"additional","affiliation":[{"name":"Hospital Therapy Department, Kazan State Medical University, 420012 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0888-2861","authenticated-orcid":false,"given":"Yulia","family":"Gordeeva","sequence":"additional","affiliation":[{"name":"Research Laboratory \u201cMedical Digital Images Based on the Basic Model\u201d, Department of Bioengineering, Institute of Living Systems, Don State Technical University, 344000 Rostov-on-Don, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chizaram","family":"Nwosu","sequence":"additional","affiliation":[{"name":"Research Laboratory \u201cMedical Digital Images Based on the Basic Model\u201d, Department of Bioengineering, Institute of Living Systems, Don State Technical University, 344000 Rostov-on-Don, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1687-4100","authenticated-orcid":false,"given":"Anastasia","family":"Tolmacheva","sequence":"additional","affiliation":[{"name":"Faculty Therapy Department Named after Professor G.D. Zalessky, Novosibirsk State Medical University, 630091 Novosibirsk, Russia"},{"name":"Medical Rehabilitation Department, Novosibirsk Regional Clinical Hospital of War Veterans No. 3, 630005 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1134\/S1990747821020069","article-title":"Structure and Functions of Gap Junctions and Their Constituent Connexins in the Mammalian CNS","volume":"15","author":"Kirichenko","year":"2021","journal-title":"Biochem. Moscow Suppl. Ser. A Membr. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Liang, Z., Wang, X., Hao, Y., Qiu, L., Lou, Y., Zhang, Y., Ma, D., and Feng, J. (2020). The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions. Front. 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