The Novel cPLA2 Inhibitor AK106-001616 Has a Protective Effect on SOD1^G93A-Induced Cell Death in NSC34 Murine Motor Neuron-Like Cell

Abstract

The expression of cytosolic phospholipase A2 (cPLA2) expression is up-regulated in animal model of ALS and in patients with familial amyotrophic lateral sclerosis (fALS). Inhibition of cyclooxygenase 2 (COX2), which is a downstream enzyme of cPLA2, ameliorates the impairment of motor function in the ALS model mice. Therefore, the arachidonic acid cascade, including the cPLA2-COX2 pathway, is an important therapeutic target of ALS. The current study was designed to investigate the potential of AK106-001616, an inhibitor of cPLA2, in protection of motor neuron cell death induced by mutant superoxide dismutase (SOD1 G93A ). AK106-001616 (1 - 10 μM) protected NSC34 cells (mouse motor neuron like cells) against SOD1 G93A -induced motor neuron cell death. Furthermore, aspirin, an inhibitor of COX1/2, reduced the SOD1 G93A -induced motor neuron cell death at a concentration that inhibited COX2. Celecoxib, a selective COX2 inhibitor, also reduced the SOD1 G93A -induced motor neuron cell death. These results suggest that the arachidonic acid cascade is important for SOD1 G93A -induced motor neuron cell death and AK106-001616 has a potent neuroprotective effect against it. AK106-001616 may be a useful therapeutic agent against SOD1 G93A -induced ALS.