Purinergic2 receptors (P2Rs) may play a key role in the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD), suggesting this process as a potential therapeutic target, according to a study recently published in Neurotherapeutics.

“This mechanism is of relevance for the use of purinergic inhibitors in ex vivo and in vivo models of autoimmunity and may encourage research for novel and more efficient derivatives that can be used without safety concerns in humans,” the authors wrote.

This experimental study analyzed the outcomes of using P2R inhibitors in a mouse model of NMOSD. An in vivo 2-photon microscopy revealed that P2R inhibitors successfully protected astrocytes against an aquaporin 4 (AQP4) and immunoglobulin G (IgG)-mediated complement activation by preventing their binding and directly interacting with IgG in a dose-dependent fashion.


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Additionally, the researchers observed evidence of antibodies unfolding after the addition of P2R inhibitors using circular dichroism spectroscopy and size-exclusion chromatography. Interestingly, not all P2R inhibitors generated the same degree of unfolding, possibly due to their varying amphiphilic properties. These findings confirm the effect these compounds may produce regarding IgG conformational change.

Read more about NMOSD etiology

“We report here that P2R inhibitors are able to protect [central nervous system] cells from antibody-mediated autoimmune attacks by partial unfolding of AQP4- and [myelin oligodendrocyte]-IgG and thus disruption of complement activation,” Kalluri et al explained.

Even though these drugs have been previously used to modulate the immune response as a treatment for multiple inflammatory diseases, it has never been used for NMOSD.

Although these results are promising for such an incapacitating disease, efforts should continue to develop optimized P2R inhibitors since side effects are considerable due to their binding capacity in multiple off-target proteins such as GABA receptors and massive binding to IgG, which could potentially lead to immune disorders. Renal and liver toxicity are other known adverse effects.

Moreover, the use of P2Rs may be highly beneficial during an NMOSD attack, especially in the acute onset phase, since in the presence of a greater leakage of the blood-brain barrier along with increased complement activation, characteristic of this stage, purinergic antagonists could aid other therapeutic agents in achieving a more specific complement-modifying action.

Reference

Kalluri S, Srivastava R, Kenet S, et al. P2R Inhibitors prevent antibody-mediated complement activation in an animal model of neuromyelitis optica. Neurotherapeutics. Published online July 12, 2022. doi:10.1007/s13311-022-01269-w