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HEME : Health and Medical Journal pISSN : 2685 Ae 2772 eISSN : 2685 Ae 404x Available Online at : https://jurnal.
id/index.
php/heme/issue/view/80 Vitamin D and Traumatic Brain Injury:
A Systematic Review of Preclinical Evidence Lieka Nugrahi Jaslindo1*.
Widia Sari1.
Alief Dhuha1.
Kurnia Maidarmi Handayani2.
Ghaniyyatul Khudri3.
Annisa Lidra Maribeth4 Department of Anatomy.
Physiology, and Radiology.
Faculty of Medicine.
Universitas Baiturrahmah.
Padang.
Indonesia Department of Biochemistry and Nutrition.
Faculty of Medicine.
Universitas Baiturrahmah.
Padang.
Indonesia Department of Histology and Immunology.
Faculty of Medicine.
Universitas Baiturrahmah.
Padang.
Indonesia Department of Public Health.
Faculty of Medicine.
Baiturrahmah University.
Padang.
Indonesia E-mail : liekanugrahijaslindo@fk.
Abstract Traumatic Brain Injury (TBI) triggers multiple secondary injury processes, such as inflammation, oxidative stress, apoptosis, b disruption, and impaired autophagy.
These mechanisms contribute to progressive neuronal damage and functional decline.
Vitamin D has emerged as a potential multi-target neuroprotective agent due to its regulatory roles in immune signaling, oxidative balance, neuronal survival, and autophagy pathways.
This systematic review synthesized preclinical evidence evaluating the effects of Vitamin D supplementation in animal models of TBI.
A comprehensive search of PubMed.
OVID, and ProQuest identified six eligible studies.
Across diverse dosing regimens and formulations.
Vitamin D consistently improved key TBI outcomes.
Reported benefits included reduced apoptosis, decreased neuroinflammation, attenuation of oxidative stress, preservation of b integrity, restoration of autophagy flux, and enhanced cognitive performance.
Mechanistically.
Vitamin D influenced several pathways, including Nrf2 activation.
TLR4/MyD88/NF-B suppression, mTOR and TRPM2 normalization, and improved microglial polarization.
Although methodological quality varied, most studies demonstrated moderate rigor and supported the neuroprotective actions of Vitamin D.
Heterogeneity in injury models, dosing strategies, and outcome measures limits direct comparison and highlights the need for standardized experimental approaches.
Overall, current preclinical evidence indicates that Vitamin D confers robust neuroprotection following TBI.
Further studies examining its mechanistic pathways, optimal therapeutic windows, and translational potential are warranted to inform future clinical applications.
Keywords: traumatic brain injury.
Vitamin D, neuroinflammation, oxidative stress, neuroprotection, animal Abstrak Cedera Otak Traumatis (TBI) memicu berbagai proses cedera sekunder, seperti peradangan, stres oksidatif, apoptosis, gangguan sawar darah otak .
, dan gangguan autofagi.
Mekanisme ini berkontribusi pada kerusakan neuron progresif dan penurunan fungsi.
Vitamin D telah muncul sebagai agen neuroprotektif multitarget potensial karena peran pengaturannya dalam pensinyalan imun, keseimbangan oksidatif, kelangsungan hidup neuron, dan jalur autofagi.
Tinjauan sistematis ini mensintesis bukti praklinis yang mengevaluasi efek suplementasi Vitamin D pada model hewan TBI.
Pencarian komprehensif di PubMed.
OVID, dan ProQuest mengidentifikasi enam studi yang memenuhi syarat.
Di berbagai rejimen dosis dan formulasi.
Vitamin D secara konsisten meningkatkan hasil utama TBI.
Manfaat yang dilaporkan termasuk pengurangan apoptosis, penurunan neuroinflamasi, pengurangan stres oksidatif, pelestarian integritas b, pemulihan aliran autofagi, dan peningkatan kinerja kognitif.
Secara mekanistik.
Vitamin D memengaruhi beberapa jalur, termasuk aktivasi Nrf2, penekanan TLR4/MyD88/NF-B, normalisasi mTOR dan TRPM2, serta peningkatan polarisasi mikroglia.
Health and Medical Journal HEME.
Vol Vi No 1 January 2026 Meskipun kualitas metodologis bervariasi, sebagian besar studi menunjukkan ketelitian yang moderat dan mendukung tindakan neuroprotektif Vitamin D.
Heterogenitas dalam model cedera, strategi dosis, dan ukuran hasil membatasi perbandingan langsung dan menyoroti perlunya pendekatan eksperimental yang terstandarisasi.
Secara keseluruhan, bukti praklinis saat ini menunjukkan bahwa Vitamin D memberikan neuroproteksi yang kuat setelah cedera otak traumatis (TBI).
Studi lebih lanjut yang meneliti jalur mekanistiknya, jendela terapeutik optimal, dan potensi translasionalnya diperlukan untuk memberikan informasi bagi aplikasi klinis di masa Kata kunci: cedera otak traumatis.
Vitamin D, neuroinflamasi, stres oksidatif, neuroproteksi, model hewan Email : heme@unbrah.
Heme.
Vol Vi No 1
January 2026
INTRODUCTION
Traumatic brain injury (TBI) remains a major global health burden and is associated with substantial long-term neurological and cognitive impairments.
1 While the primary mechanical insult occurs at the moment of impact, much of the subsequent damage arises from secondary injury processes that evolve over hours to days.
These processes include apoptosis, cerebral edema, bloodAebrain barrier .
disruption, and impairment of cellular homeostatic pathways such as Together, these mechanisms contribute to progressive neuronal loss and persistent functional deficits.
2 Given the complexity of these interacting pathways, therapies that modulate multiple biological targets may offer greater therapeutic potential than single-pathway interventions.
Vitamin D has emerged as a promising candidate in this context.
Beyond its classical role in calcium metabolism.
Vitamin D influences immune regulation, neuronal survival, oxidative balance, and inflammatory 3 The presence of Vitamin D receptors in neurons and glial cells indicates that Vitamin D can modulate key molecular pathways implicated in TBI pathophysiology, including Nrf2 signaling.
TLR4/MyD88/NFB activation, mTOR regulation, and autophagy function.
4 These pleiotropic actions provide a strong rationale for examining its neuroprotective potential.
However, findings across studies remain For example, clinical research in chronic kidney disease demonstrated vascular protective effects of Vitamin D through inflammation, supporting its mechanistic role in tissue remodeling.
5 In contrast, large-scale analyses across diverse populations reported variable associations between Vitamin D status and inflammatory biomarkers or clinical outcomes, suggesting possible influences of genetic factors, baseline levels, or methodological differences.
6 This discrepancy highlights the need for systematic synthesis of preclinical evidence to determine whether the observed effects are consistent across experimental conditions.
This gap highlights the importance of synthesizing animal studies that evaluate Vitamin D in TBI.
Differences in study design and outcome measures must be carefully considered to determine whether Vitamin D provides reliable benefits in secondary brain The present review, therefore aims to bring together existing preclinical evidence on the effects of Vitamin D on inflammation, oxidative stress, neurological function, and other key outcomes following TBI in animal The central question is how Vitamin mechanisms in experimental TBI.
II.
METHODS
This systematic literature review followed established standards for preclinical evidence synthesis and adhered to the PICO framework7, which guided the selection of the population, intervention, and comparison groups.
comprehensive search was conducted in PubMed.
OVID, and ProQuest using combinations of keywords related to TBI, animal experimentation, and Vitamin D supplementation based on the Prisma Guideline.
8 This search, completed on November 25, 2025, included articles without time restrictions.
Inclusion and exclusion criteria were defined before the screening process.
Eligible studies involved rodent models with experimentally induced TBI through methods such as controlled cortical impact, weight-drop injury, or closed-skull impact.
Only studies administering Vitamin D supplementation as the sole intervention and comparing it with placebo, vehicle, or untreated TBI groups were Relevant outcomes had to address aspects of TBI pathology, including structural brain damage, cognitive performance.
Health and Medical Journal HEME.
Vol Vi No 1 January 2026 inflammatory responses, oxidative stress, or indicators of tissue repair.
Studies involving humans, combination therapies, missing control groups, or unrelated outcomes were excluded, along with reviews, conference abstracts, and non-experimental reports.
Study selection was conducted by two independent reviewers who screened titles and abstracts, followed by full-text evaluation of potentially eligible articles.
Disagreements were resolved through discussion or consultation with an expert.
A standardized data extraction form ensured consistency in capturing information on study characteristics Additional randomization, blinding, and sample-size justification, was recorded when available.
Data concerning the accuracy, sensitivity, and detection thresholds of laboratory assays, including ELISA.
TUNEL staining, and Western blotting, were documented to support the appraisal of methodological quality.
Only studies using vertebrate animal models were Although this review did not involve direct animal experimentation, all included studies were required to report approval from Institutional Animal Care and Use Committees.
Institutional Review Boards, or equivalent ethics committees.
A narrative synthesis was conducted due to substantial methodological and clinical heterogeneity across studies.
Differences in TBI models.
Vitamin D formulations and dosing regimens, timing of administration, outcome domains, made statistical pooling These variations precluded meaningful meta-analytic comparison, and descriptively and presented in tables.
RESULT
A total of 170 records were identified across all databases, and after duplicate removal and screening, six studies met all eligibility criteria and were included in the final Email : heme@unbrah.
The study selection process is presented in Figure 1, which outlines the number of records identified, screened, excluded, and retained for qualitative To contextualize the interventions examined in the included studies, it is important to note that Vitamin D supplementation can be administered in several biochemical forms.
Calcitriol .
,25(OH)CCDCE) represents the active hormonal metabolite that directly binds to the Vitamin D Receptor (VDR), while Cholecalciferol (Vitamin DCE) acts as a precursor that requires hepatic and renal hydroxylation to become biologically active.
Some studies administered Vitamin D in an identification of the biochemical type used.
These distinctions are relevant because different formulations may exert variable pharmacokinetic and biological effects following TBI.
Vitamin D metabolism involves multiple forms with distinct physiological roles.
Vitamin DCE .
is the primary source for humans and animals, synthesized in the skin through sunlight exposure and obtained from dietary or supplemental Vitamin DCC .
is derived from plant-based foods and certain After absorption, both forms are converted in the liver to calcidiol .
OHD), the main circulating marker used to assess Vitamin D status.
Calcidiol is then transformed in the kidneys into calcitriol
,25(OH)CCDCE),
inflammatory, and neuroprotective processes.
Inactive metabolites, including 24,25(OH)CCD and calcitroic acid, are subsequently produced and excreted.
9 Understanding these metabolic steps provides context for interpreting the diverse Vitamin D formulations administered in TBI studies.
Across the six included studies, controlled cortical impact and weight-drop models were Heme.
Vol Vi No 1 January 2026 used in mice and rats to induce TBI.
Vitamin D was administered either as calcitriol, cholecalciferol, or unspecified Auvitamin D supplementation,Ay using intraperitoneal injections or oral gavage.
Despite variations in animal species, injury severity, dose regimens, and timing of treatment, the studies consistently demonstrated beneficial effects of Vitamin D on post-TBI outcomes.
The characteristics of all included studies, including species, strain, sample size, injury model, intervention details, comparator groups, and outcome domains, are summarized in the Table 2.
Methodological quality was appraised using the CAMARADES checklist.
10 Reported adherence to randomization, blinding, allocation concealment, compliance with animal welfare regulations, and sample size calculation varied substantially across Studies that provided detailed descriptions of anesthetic procedures, temperature control, and outcome assessor blinding achieved higher quality scores, whereas incomplete reporting of group justification, and missing statements of conflict of interest contributed to lower scores in others.
Overall, the included studies demonstrated moderate methodological rigor, with several high-quality studies providing neuroprotective role of Vitamin D in experimental TBI (Supplementary fil.
Across studies.
Vitamin D supplementation improved multiple facets of TBI pathology.
Several neurological function, reduced apoptosis, and restoration of autophagy flux following calcitriol administration.
11Ae13 Improvements in spatial learning and memory were reported in studies employing Morris Water Maze tasks, particularly when Vitamin D modulated VDR expression.
NOX2 activity, or Nrf2 11,13,14 Anti-inflammatory effects were observed in studies measuring cytokine levels, where Vitamin D decreased TNF-.
IL-1, and IL-6 concentrations or increased IL-10 expression.
14Ae16 Additional protective mechanisms included attenuation of oxidative stress11,13,16, b integrity14,16, reduction of brain edema14, modulation of microglial polarization,16 and enhancement of neuronal survival12,13.
Although the magnitude of benefit varied, the direction of effect was uniformly favorable across all studies.
FIGURE 1 PRISMA
IV.
DISCUSSION