Purinergic P2X₇ Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by upper and lower motor neuron loss. The pathomechanisms of ALS are still poorly understood with current hypotheses involving genetic mutations, excitotoxicity, and reactive oxygen species formation. In the absence of a disease-altering clinically approved therapeutic, there is an ever-increasing need to identify new targets to develop drugs that delay disease onset and/or progression. The purinergic P2X7 receptor (P2X7R) has been implicated widely across the ALS realm, providing a potential therapeutic strategy. This review summarizes the current understanding of ALS, the P2X7R and its role in ALS, the current landscape of P2X7R antagonists, and the in vivo potential of these antagonists in preclinical ALS models.

Origin, distribution, and function of three frequent coding polymorphisms in the gene for the human P2X7 ion channel

“…P2X7 has been proposed as a therapeutic target for a variety of infectious (Di Virgilio et al, 2017), inflammatory (Arulkumaran et al, 2011;Adinolfi et al, 2018;Burnstock and Knight, 2018;Magalhaes and Castelucci, 2021;Verma et al, 2022), autoimmune (Cao et al, 2019), bone (Zeng et al, 2019;Dong et al, 2020), muscular (Gorecki, 2019), cardiovascular (Chen et al, 2018;Cisneros-Mejorado et al, 2020;Shokoples et al, 2021), oncological (Burnstock and Knight, 2018;Li et al, 2020;Drill et al, 2021;Pegoraro and Adinolfi, 2021;Zhu et al, 2021) and neurologic diseases (Rech et al, 2016;Bhattacharya, 2018, Domercq and Matut,e 2019, Engel et al, 2021, including COVID-19 (Pacheco and Faria, 2021), rheumatoid arthritis (Baroja-Mazo and Pelegrin, 2012;McInnes et al, 2014), diabetic retinopathy (Tassetto et al, 2021), alcoholic liver disease (Le Dare et al, 2021), Alzheimer (Illes et al, 2019) and depression (Deussing and Arzt, 2018;Wei et al, 2018;Huang and Tan, 2021), multiple sclerosis (Domercq and Matute, 2019), amyotrophic lateral sclerosis (Sluyter et al, 2017;McKenzie et al, 2022). Our results indicate that it may be wise to monitor the genotype of P2RX7 and the ATPsensitivity of its gene product P2X7 in clinical studies designed to evaluate the therapeutic benefit of P2X7-targeting drugs and antibodies (Bartlett et al, 2014;De Marc...…”

Amyotrophic Lateral Sclerosis in Long-COVID Scenario and the Therapeutic Potential of the Purinergic System in Neuromodulation

“…Even though it is a widely debated pathology, considerable challenges remain in the development of therapies capable of modifying the course of ALS. Given this scenario, there is a growing need to identify new targets for creating drugs that can delay the onset and progression of this pathology [9,10]. In this context, the importance of the purinergic system is highlighted, and the feasibility of developing medications targeted at these receptors as a possible therapeutic approach for ALS is discussed [11].…”

“…Dysregulation of this system is closely associated with neurodegenerative and neuroinflammatory diseases, with ALS being one of the conditions included in this spectrum. In this context, purinergic receptors have been widely studied to identify their role in this pathology and possible alternative therapeutic strategies [9,11,12].…”

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

“…P2X7 (purinergic receptor) provides an advantage over TSPO and is successfully able to differentiate between both forms of microglia, and is selectively expressed in pro-inflammatory M1 microglia rather than the anti-inflammatory M1 microglial form. Purinergic receptor showed its superiority for both imaging and therapeutics (Mckenzie et al, 2022;Rotondo et al, 2022) The cyanoguanidine analog, A-740003, a racemic substance designed to treat neuropathic pain, served as the basis for the initial known attempt to produce a P2X7 PET-imaging agent.…”