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Author Spotlight: Unveiling the Pathway Linking Obesity to Autoimmune Inflammation in Multiple Sclerosis
Published on: February 23, 2024
Effect of sildenafil on neuroinflammation and synaptic plasticity pathways in experimental autoimmune
Shyrlene Meiry da Rocha Araújo1, Eduardo Duarte-Silva2, Crislayne Gonçalo de Santana Marinho3
1Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil; Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), PE, Brazil.
Abstract:
Multiple sclerosis (MS) is a chronic immuno-inflammatory disease of the central nervous system characterized by demyelination and axonal damage. Cognitive changes are common in individuals with MS since inflammatory molecules secreted by microglia interfere with the physiological mechanisms of synaptic plasticity. According to previous data, inhibition of PDE5 promotes the accumulation of cGMP, which inhibits neuroinflammation and seems to improve synaptic plasticity and memory. The present study aimed to evaluate the effect of sildenafil on the signaling pathways of neuroinflammation and synaptic plasticity in experimental autoimmune encephalomyelitis (EAE). C57BL/6 mice were divided into three experimental groups (n = 10/group): (a) Control; (b) EAE; (c) EAE + sild (25 mg/kg/21 days). Sildenafil was able to delay the onset and attenuate the severity of the clinical symptoms of EAE. The drug also reduced the infiltration of CD4+ T lymphocytes and their respective IL-17 and TNF-α cytokines. Moreover, sildenafil reduced neuroinflammation in the hippocampus (assessed by the reduction of inflammatory markers IL-1β, pIKBα and pNFkB and reactive gliosis, as well as elevating the inhibitory cytokines TGF-β and IL-10). Moreover, sildenafil induced increased levels of NeuN, BDNF and pCREB, protein kinases (PKA, PKG, and pERK) and synaptophysin, and modulated the expression of the glutamate receptors AMPA and NMDA. The present findings demonstrated that sildenafil has therapeutic potential for cognitive deficit associated with multiple sclerosis.
Insights
Sildenafil, a PDE5 inhibitor, shows promise in treating cognitive deficits in multiple sclerosis (MS) by reducing neuroinflammation and improving synaptic plasticity in experimental models.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a central nervous system disorder causing cognitive impairment due to neuroinflammation and synaptic plasticity disruption.
- Phosphodiesterase type 5 (PDE5) inhibition may counteract neuroinflammation and enhance synaptic plasticity and memory.
Purpose of the Study:
- To investigate the therapeutic effects of sildenafil on neuroinflammation and synaptic plasticity in experimental autoimmune encephalomyelitis (EAE), an MS model.
- To assess sildenafil's impact on cognitive function and related molecular pathways in EAE.
Main Methods:
- C57BL/6 mice were induced with EAE and treated with sildenafil (25 mg/kg for 21 days) or vehicle.
- Evaluated clinical EAE scores, immune cell infiltration (CD4+ T lymphocytes), cytokine levels (IL-17, TNF-α, IL-1β, TGF-β, IL-10), glial activation, and synaptic plasticity markers (NeuN, BDNF, pCREB, synaptophysin, glutamate receptors).
Main Results:
- Sildenafil delayed EAE onset, reduced clinical severity, and decreased CD4+ T cell infiltration and pro-inflammatory cytokines.
- The drug significantly reduced hippocampal neuroinflammation, reactive gliosis, and elevated anti-inflammatory cytokines.
- Sildenafil increased levels of neuronal markers, neurotrophic factors, and synaptic proteins, while modulating glutamate receptor expression.
Conclusions:
- Sildenafil demonstrates significant therapeutic potential for mitigating cognitive deficits associated with multiple sclerosis.
- Its mechanisms involve suppressing neuroinflammation and enhancing synaptic plasticity pathways.
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