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Neuroprotective Role of Vitamin D Against LPS-Induced Cognitive Deficits in Rats: Targeting Hippocampal PERK-ATF4-CHOP-Mediated ER Stress and Calcium Dyshomeostasis
EL-Salamony GI, Mohamed RH, Saad RA, Tarek M, Fawzy NM, Elnahas EM.. Research Square, 2026-10-08
Topic: Gut, metabolism and diet
Although endoplasmic reticulum (ER) stress and maladaptive unfolded protein response (UPR) are increasingly implicated in Alzheimer’s disease (AD), the influence of vitamin D (VitD) on these mechanisms remains unclear. Therefore, this study aimed to investigate the impact of VitD on cognitive dysfunction and hippocampal ER stress induced by lipopolysaccharide (LPS), with special emphasis on the PERK signaling pathway of UPR as well as hippocampal calcium homeostasis. Rats were assigned to three groups: Control, LPS (250 µg/kg, i.p., 7 days), and VitD-LPS (VitD 500 IU/kg, oral gavage for 7 days before LPS, continued during LPS administration, and throughout the final week of neurobehavioral testing until sacrifice). Behavioral performance and hippocampal molecular and biochemical markers, as well as histological assessments, including immunohistochemical and histomorphometric analyses, were evaluated. LPS-treated rats exhibited cognitive impairment, increased levels of hippocampal Aβ₁-₄₂, p-tau, TNF, and GFAP, along with reduced hippocampal CA1 thickness. These changes were accompanied by hippocampal ER stress/UPR dysregulation (increased GRP78, p-PERK, ATF4, and CHOP) and Ca²⁺ dysregulation (increased RyR2 expression and calpain), together with diminished ATP levels, impaired autophagy-related activity (reduced Beclin-1), and enhanced cell death-related changes (increased caspase-3). In contrast, VitD supplementation improved cognitive function and attenuated these associated LPS-induced hippocampal abnormalities. In conclusion, VitD exerted a multifaceted protective effect against LPS-induced cognitive dysfunction, suggesting VitD as a promising approach for mitigating AD-related cognitive decline, potentially involving attenuation of hippocampal neuroinflammation and ER stress, with modulation of the PERK-ATF4-CHOP pathway, and alleviation of Ca²⁺ dysregulation.
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APA 7th
EL-Salamony, G. I., Mohamed, R. H., Saad, R. A., Tarek, M., Fawzy, N. M., & Elnahas, E. M. (2026). Neuroprotective Role of Vitamin D Against LPS-Induced Cognitive Deficits in Rats: Targeting Hippocampal PERK-ATF4-CHOP-Mediated ER Stress and Calcium Dyshomeostasis. Research Square. https://doi.org/10.21203/rs.3.rs-10413434/v1
Vancouver
EL-Salamony GI, Mohamed RH, Saad RA, Tarek M, Fawzy NM, Elnahas EM. Neuroprotective Role of Vitamin D Against LPS-Induced Cognitive Deficits in Rats: Targeting Hippocampal PERK-ATF4-CHOP-Mediated ER Stress and Calcium Dyshomeostasis. Research Square. 2026. doi:10.21203/rs.3.rs-10413434/v1.
BibTeX
@article{elsalamony2026-a10c51b4,
author = {EL-Salamony, G. I. and Mohamed, R. H. and Saad, R. A. and Tarek, M. and Fawzy, N. M. and Elnahas, E. M.},
title = {{Neuroprotective Role of Vitamin D Against LPS-Induced Cognitive Deficits in Rats: Targeting Hippocampal PERK-ATF4-CHOP-Mediated ER Stress and Calcium Dyshomeostasis}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10413434/v1},
url = {https://doi.org/10.21203/rs.3.rs-10413434/v1}
}
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Key findings
- In conclusion, VitD exerted a multifaceted protective effect against LPS-induced cognitive dysfunction, suggesting VitD as a promising approach for mitigating AD-related cognitive decline, potentially involving attenuation of hippocampal neuroinflammation and ER stress, with modulation of the PERK-ATF4-CHOP pathway, and alleviation of Ca²⁺ dysregulation.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “rats”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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