AFC-5128 - LARVOL DELTA

The P2X7R-antagonist AFC-5128 ameliorates chronic experimental autoimmune encephalomyelitis in a preventive and therapeutic paradigm. (PubMed, Front Immunol) - "In vivo, MOG35-55 immunized C57BL/6 mice were treated with AFC-5128, fingolimod (FTY) or vehicle in different treatment paradigms. Mechanistically, calcium influx of microglia was reduced following AFC-5128 treatment, which implies the ability of AFC-5128 to stabilize calcium homeostasis. Therefore, therapeutic inhibition of P2X7R via AFC-5128 has the potential for translation into a treatment of both relapsing and progressive forms of multiple sclerosis."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis

P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice. (PubMed, Theranostics) - "To test the anti-epileptogenic effects of P2X7R antagonism, mice were treated with brain-penetrant P2X7R antagonists JNJ-54175446 (30 mg/kg) or AFC-5128 (30 mg/kg) for 7 days post-CCI. Finally, P2X7R radioligand uptake after TBI correlated with seizure threshold at 3 weeks post-injury. Our results demonstrate the antiepileptogenic potential of P2X7R antagonism to prevent TBI-induced epilepsy and indicate that P2X7R-based PET imaging may be a useful diagnostic tool to identify people at risk of developing PTE."

Journal • Preclinical • CNS Disorders • Epilepsy • Vascular Neurology • CX3CR1

The P2X7R-antagonist AFC-5128 ameliorates chronic experimental autoimmune encephalomyelitis in a preventive and therapeutic paradigm with implications for neuroprotection (MSMilan 2023) - "Fingolimod was administered as a positive control. Treatment of EAE mice with AFC-5128 dose-dependently ameliorates chronic EAE both after early and late therapeutic intervention associated with moderate effects on markers of inflammatory and alternative activation of microglia. Mechanistically, calcium influx of microglia was reduced following AFC-5128 treatment, which implies stabilizing effects of calcium homeostasis. Based on these results, therapeutic inhibition of P2X7R using AFC-5128 has therefore implications for neuroprotection with the potential for translation into a treatment of both relapsing and progressive forms of multiple sclerosis."

CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • CD163 • CD68 • CD86 • MRC1

Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived astrocytes. (PubMed, Purinergic Signal) - "Importantly, stimulation with the potent non-selective P2X7R agonist 2',3'-O-(benzoyl-4-benzoyl)-adenosine 5'- triphosphate (BzATP) or endogenous agonist ATP induced robust calcium rises in hiPSC-derived astrocytes which were blocked by the selective P2X7R antagonists AFC-5128 or JNJ-47965567. Our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived astrocytes and support their in vitro utility in investigating the role of the P2X7R and drug screening in disorders of the central nervous system (CNS)."

Journal • CNS Disorders • GFAP

Increased expression of the ATP-gated P2X7 receptor reduces responsiveness to anti-convulsants during status epilepticus in mice. (PubMed, Br J Pharmacol) - "Our results demonstrate that P2X7R-induced pro-inflammatory effects contribute to resistance to pharmacotherapy during status epilepticus and suggest therapies targeting the P2X7R as novel adjunctive treatments for drug-refractory status epilepticus."

Journal • Preclinical • Epilepsy • Immunology • Inflammation