New MS Study Seeks To Understand How Inflammation Causes Neuronal Damage in Multiple Sclerosis

A team of researchers from Italy recently examined if p53 genetic variants influence synaptic and toxic effects of cytokines in the neurodegenerative processes that occurs in Multiple Sclerosis. The study, entitled “Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53,” was recently published in the journal Molecular Neurodegeneration.

Evidence shows that the immune and central nervous systems are related. This is because the effector immune cells are regulated by neurotransmissions, and cytokine signaling is known to modulate function such as neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, as well as the neural circuitry of cognition and mood.

The neuroinflammation that occurs in neurodegenerative diseases such as multiple sclerosis (MS) is caused by proinflammatory cytokines, such as tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β). Recent studies have found that IL-1β plays a role in MS-associated neurodegenerative damage and clinical progression.

In this regard, it is crucial to understand how inflammation causes neuronal damage in multiple sclerosis (MS).

Proinflammatory cytokines are able to induce p53, and are involved in the enhancement of p53-mediated apoptosis. By investigating how p53 genetic variants influence the synaptic and toxic effects of proinflammatory cytokines, the researchers thought that it is possible to provide further insights into the pathophysiology of the neurodegenerative damage that occurs in MS.

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In the study, the researchers specifically examined the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients.

The results indicated that IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by an inhibitor of p53.

Additionally, a protein kinase C pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation relevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a recognized downstream target of activated p53.

Moreover, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, retracted the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients.

The interaction between p53 and CSF IL-1β showed that IL-1β-driven neurodegenerative damage, caused alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype.

The researchers indicate that inflammatory synaptopathy and neurodegeneration caused by IL-1β in patients with RRMS involve the apoptotic cascade. In this regard, potential therapeutics targeting the interaction between IL-1β-p53 may have a neuroprotection effect in patients with multiple sclerosis.