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1- Department of Physical Education and Sports Sciences, University of Qom, Qom, Iran.
Abstract: (4 Views)
Objective: Diabetes is associated with memory impairment, reduced synaptic plasticity, and damage to components of the hippocampal neurovascular unit. Most previous studies have examined only total levels of brain-derived neurotrophic factor (BDNF) or the TrkB receptor, whereas the balance between mature BDNF and proBDNF, TrkB isoforms, receptor phosphorylation, and responses across different cell types may change independently. The present study aimed to systematically investigate the multilevel dysregulation of the BDNF/TrkB axis in the diabetic hippocampus and to integrate evidence on the effects of high-intensity interval training (HIIT) and spirulina with publicly available transcriptomic data.
Materials and Methods: Preclinical studies published up to June 14, 2026, were searched in PubMed/MEDLINE, Scopus, Web of Science, and Embase. Ultimately, 19 animal studies reporting direct hippocampal outcomes related to the BDNF/TrkB axis were included in the main synthesis, while one vascular study was considered as complementary mechanistic evidence. Risk of bias was assessed using the SYRCLE tool. In addition to the systematic review, processed data from GSE125387 were exploratorily reanalyzed at the sample level. Findings from the cellular clusters of GSE234278 and endothelial evidence from GSE241142 and GSE241693 were also extracted from the corresponding articles and supplementary files and incorporated into a structured evidence synthesis.
Results: In most studies, diabetes reduced mature BDNF and p-TrkB and decreased ERK/CREB activity. However, changes in Bdnf mRNA, proBDNF, and total TrkB were heterogeneous. In GSE125387, 44 genes met differential expression criteria in diabetes-versus-control and 961 in intervention-versus-diabetes comparisons. Changes in Bdnf and Ntrk2 were statistically significant in some comparisons but had small effect sizes and did not meet the prespecified threshold (FDR < 0.05, |log2FC| ≥ 0.5); notably, Bdnf direction differed between the linear model and pairwise group means. In GSE234278, neurotrophic gene changes differed across neuronal and glial clusters. GSE241142/GSE241693 supported endothelial dysfunction and possible sex-dependent differences. HIIT/HIIE studies predominantly increased BDNF and improved cognition, whereas spirulina modulated proBDNF/p75NTR signaling, inflammation, and apoptosis. No study directly compared HIIT and spirulina in a factorial design, so synergy remains unproven.
Conclusion: Neurotrophic dysfunction in the diabetic hippocampus cannot be explained solely by reduced total BDNF. Evidence supports a lack of coordination among ligand processing, receptor abundance/activation, downstream signaling, and neurovascular unit cell states. HIIT and spirulina may target complementary components, but synergy is unproven. The TrkB-FL/TrkB-T1 balance and p-AKT status remain largely unmeasured and should be regarded as hypothesized. Future studies should simultaneously assess mature BDNF/proBDNF, TrkB-FL/TrkB-T1, p-TrkB/TrkB, p-AKT and p-CREB, and cell-type-specific responses in both sexes.
Materials and Methods: Preclinical studies published up to June 14, 2026, were searched in PubMed/MEDLINE, Scopus, Web of Science, and Embase. Ultimately, 19 animal studies reporting direct hippocampal outcomes related to the BDNF/TrkB axis were included in the main synthesis, while one vascular study was considered as complementary mechanistic evidence. Risk of bias was assessed using the SYRCLE tool. In addition to the systematic review, processed data from GSE125387 were exploratorily reanalyzed at the sample level. Findings from the cellular clusters of GSE234278 and endothelial evidence from GSE241142 and GSE241693 were also extracted from the corresponding articles and supplementary files and incorporated into a structured evidence synthesis.
Results: In most studies, diabetes reduced mature BDNF and p-TrkB and decreased ERK/CREB activity. However, changes in Bdnf mRNA, proBDNF, and total TrkB were heterogeneous. In GSE125387, 44 genes met differential expression criteria in diabetes-versus-control and 961 in intervention-versus-diabetes comparisons. Changes in Bdnf and Ntrk2 were statistically significant in some comparisons but had small effect sizes and did not meet the prespecified threshold (FDR < 0.05, |log2FC| ≥ 0.5); notably, Bdnf direction differed between the linear model and pairwise group means. In GSE234278, neurotrophic gene changes differed across neuronal and glial clusters. GSE241142/GSE241693 supported endothelial dysfunction and possible sex-dependent differences. HIIT/HIIE studies predominantly increased BDNF and improved cognition, whereas spirulina modulated proBDNF/p75NTR signaling, inflammation, and apoptosis. No study directly compared HIIT and spirulina in a factorial design, so synergy remains unproven.
Conclusion: Neurotrophic dysfunction in the diabetic hippocampus cannot be explained solely by reduced total BDNF. Evidence supports a lack of coordination among ligand processing, receptor abundance/activation, downstream signaling, and neurovascular unit cell states. HIIT and spirulina may target complementary components, but synergy is unproven. The TrkB-FL/TrkB-T1 balance and p-AKT status remain largely unmeasured and should be regarded as hypothesized. Future studies should simultaneously assess mature BDNF/proBDNF, TrkB-FL/TrkB-T1, p-TrkB/TrkB, p-AKT and p-CREB, and cell-type-specific responses in both sexes.
Keywords: Diabetes Mellitus, Hippocampus, BDNF, Trkb, Neurovascular Unit, High-Intensity Interval Training, Spirulina, Transcriptomics
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