The beneficial effects of modafinil administration on repeat mild traumatic brain injury (RmTBI) pathology in adolescent male rats are not dependent upon the orexinergic system.

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE
    • Publication Information:
      Publication: Orlando Fl : Academic Press
      Original Publication: New York.
    • Subject Terms:
      Modafinil*/pharmacology ; Modafinil*/therapeutic use ; Orexins*/metabolism ; Brain Concussion*/drug therapy ; Brain Concussion*/metabolism ; Brain Concussion*/pathology ; Rats, Sprague-Dawley* ; Wakefulness-Promoting Agents*/therapeutic use ; Wakefulness-Promoting Agents*/pharmacology; Animals ; Male ; Rats
    • Abstract:
      The sleep-wake cycle plays an influential role in the development and progression of repeat mild traumatic brain injury (RmTBI)-related pathology. Therefore, we first aimed to manipulate the sleep-wake cycle post-RmTBI using modafinil, a wake-promoting substance used for the treatment of narcolepsy. We hypothesized that modafinil would exacerbate RmTBI-induced deficits. Chronic behavioural analyses were completed along with a 27-plex serum cytokine array, metabolomic and proteomic analyses of cerebrospinal fluid (CSF), as well as immunohistochemical staining in structures important for sleep/wake cycles, to examine orexin, melanin-concentrating hormone, tyrosine hydroxylase, and choline acetyltransferase, in the lateral hypothalamus, locus coeruleus, and basal forebrain, respectively. Contrary to expectation, modafinil administration attenuated behavioural deficits, metabolomic changes, and neuropathological modifications. Therefore, the second aim was to determine if the beneficial effects of modafinil treatment were driven by the orexinergic system. The same experimental protocol was used; however, RmTBI rats received chronic orexin-A administration instead of modafinil. Orexin-A administration produced drastically different outcomes, exacerbating anxiety-related and motor deficits, while also significantly disrupting their metabolomic and neuropathological profiles. These results suggest that the beneficial effects of modafinil administration post-RmTBI, work independently of its wake-promoting properties, as activation of the orexinergic wake-promoting system with orexin-A was detrimental. Overall, these findings highlight the complexity of sleep-wake changes in the injured brain and showcase the potential of the arousal and sleep systems in its treatment.
      Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
      (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Basal forebrain; Choline acetyltransferase; Concussion; Glymphatic system; Hypocretin; Lateral hypothalamus; Locus coeruleus; Melanin-concentrating hormone; Tyrosine hydroxylase
    • Accession Number:
      R3UK8X3U3D (Modafinil)
      0 (Orexins)
      0 (Wakefulness-Promoting Agents)
    • Publication Date:
      Date Created: 20240927 Date Completed: 20241024 Latest Revision: 20241024
    • Publication Date:
      20241025
    • Accession Number:
      10.1016/j.expneurol.2024.114969
    • Accession Number:
      39332798