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Treating multiple sclerosis from the neurochemical side: the French focus on glutamate excitotoxicity

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Treating multiple sclerosis from the neurochemical side: the French focus on glutamate excitotoxicity

Considering autoimmunity as the putative pathophysiology of MS, the development of treatments for MS has focused on modulation of the immune system. Acute episodes in RRMS are treated with a variety of medications including glucocorticoids and interferons beta 1a and 1b that increase anti-inflammatory cytokines, reduce proinflammatory cytokines, and reduce T cell activation. Glatiramer acetate resembles myelin basic protein and it may therefore act as a decoy to reduce T cell activation against myelin, while also altering T cell differentiation towards less inflammatory subtypes. Other immunomodulatory drugs for RRMS are the monoclonal antibodies natalizumab and mitoxantrone; the anti-CD20 drugs rituximab, ocrelizumab and ofatumumab; and the S1P inhibitor fingolimod. In contrast, there is a lack of available treatments for progressive forms of MS, characterized by chronic inflammation and neurodegeneration.

An alternative pathophysiological hypothesis is that MS is primarily or initially a neurodegenerative disease, in which the death of neurons releases myelin which in turn triggers a secondary autoimmune reaction. Neuroprotective strategies could therefore act upstream of the autoimmune mechanisms that lead to demyelination. Regardless of which model is correct, neuroprotective treatments could be effective against neurodegeneration in progressive MS and reduce autoimmunity by decreasing myelin released by dying neurons. With this strategy in mind, targeting the processes that lead to neuronal death becomes a promising prospect for developing treatments. In particular, neuroprotection against glutamate excitotoxicity is a potential avenue that could yield effective therapies. And there is growing evidence for the role of glutamate-mediated excitotoxicity in MS.

Preclinical studies conducted by CAMH using a small molecule drug have shown promise as a potential new treatment for multiple sclerosis (MS). The findings were published today in the journal Science Advances. MS is known to damage myelin, a protective sheath that forms around nerves in the brain and spinal cord. In this study, Dr. Fang Liu and her team treated MS in a completely different way, targeting the glutamate system. The study results showed that the synthesized lead compound not only reduced symptoms but can also repair damaged myelin in two different preclinical models of MS. These compounds all had good oral bioavailability (ZCAN155: 58%; ZCAN262: 90%). The addition of a second fluorine atom to compound 4 (compound 6 – ZCAN262) significantly improved human, rat, and mouse microsomal stability, and this compound was selected for further in vivo characterization.

ZCAN262 improves function The clinical use of glutamate receptor modulators is limited by the critical role of glutamate receptors in excitatory neurotransmission (25). Therefore, our promising results showing that ZCAN262 can improve neurological function and protect myelin, oligodendrocytes, and axons would not be clinically useful if ZCAN262 blocked AMPA receptor-mediated neurotransmission. Electrophysiological assays in mice showed that ZCAN262 treatment can enhance basal synaptic transmission in hippocampal circuits in a stimulus-dependent manner, although the relationship is weak and disappears when stimulus intensity is controlled. Overall, and taking into account stimulus intensity, there was no evidence that ZCAN262 treatment altered basal and neurological synaptic transmission in the cuprizone mouse model of MS, although ZCAN 155 and its precursor, YH668, also improved motor function in EAE mice.

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There are many immunomodulatory drugs used to treat RRMS, but these potential drug candidates take advantage of a different therapeutic strategy: neuroprotection. It is possible that one of the compounds mentioned could be used together with current immunological treatments and could have complementary effects. As with cancer chemotherapy drug cocktails, simultaneously targeting a disease pathway at multiple points can have synergistic effects, resulting in better outcomes and fewer side effects than monotherapy. Another potential application of these molecules could be the treatment of progressive forms of multiple sclerosis, for which there are no effective treatments available to halt the accumulation of neurological deficits and neurodegeneration.

By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

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Scientific publications

​Kamma E, Lasisi W et al. J Neuroinflamm. 2022; 19:45.

Greger IH, Watson JF et al. Neuron 2017; 94:713–730.

Sulkowski GB et al. J Neuroimmunol. 2013; 261:67–76.

Newcombe J, Uddin A et al. Brain Pathol. 2008; 18:52-61.

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