Vitamina D e acidi grassi omega-3 nella protezione neuronale: evidenze sperimentali da un modello di neurodegenerazione indotta da glutammato

Neurodegeneration represents the final outcome of a complex interaction between glutamatergic excitotoxicity, neuroinflammation, oxidative stress, and alterations in synaptic plasticity. In numerous neurological and neuropsychiatric conditions—from classic neurodegenerative diseases to neurodevelopmental disorders—overactivation of glutamatergic receptors and loss of inflammatory control significantly contribute to progressive neuronal damage.

In this context, the study published in Scientific Reports evaluated the neuroprotective effect of vitamin D and omega-3 fatty acids (EPA and DHA) in an animal model of neurodegeneration induced by monosodium glutamate (MSG). The study offers relevant insights into the role of nutrition and nutraceuticals in modulating neuroinflammatory and neurodegenerative processes.

Biological rationale and study objectives

Glutamate is the main excitatory neurotransmitter in the central nervous system. However, excessive glutamatergic stimulation can trigger excitotoxicity phenomena, with increased intracellular calcium flow, mitochondrial dysfunction, production of reactive oxygen species, and activation of the inflammatory cascade. Monosodium glutamate is commonly used in experimental models to reproduce these mechanisms of neuronal damage, particularly at the hippocampal level, a region crucial for memory, learning, and emotional processing.

Vitamin D and omega-3 are known for their immunomodulatory, anti-inflammatory, and neuroprotective properties. Vitamin D, through the VDR receptor, regulates neuronal gene expression, calcium homeostasis, and the inflammatory response. Omega-3s, particularly DHA, are structural components of neuronal membranes and precursors of pro-resolving mediators of inflammation. The study aims to assess whether their administration, alone or combined, can attenuate MSG-induced neurodegenerative damage.

Experimental design

The study was conducted on male Sprague-Dawley rats divided into experimental groups: control, MSG, MSG with vitamin D, MSG with omega-3, and MSG with the combination of vitamin D + omega-3. The treatment lasted four weeks. At the end, the animals underwent behavioral and cognitive tests, followed by histological analysis of the hippocampus, evaluation of inflammatory markers, and gene expression analysis, with particular attention to tau protein and the vitamin D receptor.

Cognitive and behavioral effects

Exposure to MSG resulted in a significant worsening of cognitive performance, with learning and memory deficits evidenced in behavioral tests. These results are consistent with hippocampal damage induced by glutamatergic excitotoxicity. Administration of vitamin D or omega-3 produced a partial improvement in cognitive functions, while the combination of the two nutrients showed a more marked recovery of memory abilities and behavioral exploration.

This finding suggests a synergistic effect, probably linked to the convergence of distinct but complementary molecular mechanisms: modulation of calcium and gene expression on one hand, membrane stabilization and reduction of inflammation on the other.

Neurodegeneration, tau, and inflammation

At the histopathological level, treatment with MSG induced significant neuronal degeneration in the hippocampus, associated with increased expression of pathological tau protein. Hyperphosphorylation and accumulation of tau represent a key element in numerous neurodegenerative conditions and are strongly influenced by the inflammatory state and oxidative stress.

The combination of vitamin D and omega-3 significantly reduced the presence of degenerated neurons and tau immunoreactivity, with a greater effect compared to individual treatments. In parallel, a reduction in pro-inflammatory cytokines such as TNF-α and IL-6 was observed, accompanied by an increase in IL-10, a cytokine with anti-inflammatory and neuroprotective action.

Role of the vitamin D receptor (VDR)

One of the most relevant aspects of the study concerns the expression of the vitamin D receptor at the hippocampal level. In rats treated with the combination of vitamin D + omega-3, VDR expression was significantly increased compared to the MSG group. This finding suggests that omega-3s may enhance vitamin D signaling, improving its biological efficacy at the neuronal level.

VDR activation is involved in the regulation of genes associated with neuronal survival, immune response, and synaptic plasticity. Therefore, the increase in its expression could represent a central node in the observed protection against excitotoxic damage.

Nutritional and clinical implications

Although this is a preclinical study, the results provide solid biological support for the use of vitamin D and omega-3 as supportive tools in modulating neuroinflammatory and neurodegenerative processes. The evidence is particularly relevant from an integrated medicine and functional nutrition perspective, where the goal is not to replace pharmacological therapy, but to support endogenous mechanisms of neuronal resilience.

In the clinical setting, these data reinforce the focus on vitamin D status and omega-3 fatty acid intake in vulnerable populations, including individuals with neuropsychiatric disorders, neurodivergence, and conditions characterized by chronic neuroinflammation.

Conclusions

The study demonstrates that the combination of vitamin D and omega-3 can attenuate glutamate-induced neurodegeneration through modulation of tau pathology, inflammatory response, and VDR-mediated signaling. These results reinforce the concept that nutrition can act as a biological modulator of brain processes, opening interesting perspectives for future clinical studies in humans.