Reduction of cytosolic phospholipase A2α upregulation delays the onset of symptoms in SOD1G93A mouse model of amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem, and spinal cord. Cytosolic phospholipase A(2) alpha (cPLA(2)alpha) upregulation and activation in the spinal cord of patients with sporadic ALS and in the spinal cord of human mutant SOD1G93A (hmSOD1) transgenic mice were recently reported. Methods: cPLA(2)alpha upregulation in the brainstem and spinal cord was reduced by brain infusion of a specific antisense oligonucleotide against cPLA(2)alpha (AS), and the effect was evaluated on disease progression and brain cell activation. Results: We found that the elevation of cPLA(2)alpha protein expression in the spinal cord was first detected at 6-week-old hmSOD1 mice and remained elevated during their whole life span. Reduction of the elevated expression of cPLA(2)alpha in the spinal cord of hmSOD1 mice by brain infusion of an AS at week 15 (shortly before the appearance of the disease symptoms), for a duration of 6 weeks, delayed the loss of motor neuron function in comparison with hmSOD1 mice and with sense brain-infused hmSOD1 mice. To characterize the effect of cPLA(2)alpha upregulation on different processes taking place at the appearance of the disease symptoms, mice were brain infused with AS or with sense at week 15 for 3-4 weeks. The AS treatment that reduced cPLA(2)alpha upregulation in the spinal cord of AS-treated hmSOD1 mice (as analyzed at week 18-19) prevented the reduction in the number of the neurons (detected by NeuN) and inhibited astrocyte activation (detected by GFAP) and microglia activation (detected by Iba-1 and by CD40). In addition, AS treatment blunted the upregulation of the proinflammatory enzyme-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) detected in hmSOD1 mice. Conclusions: Since specific reduction of cPLA(2)alpha in the brainstem and spinal cord significantly attenuated the development of the disease, cPLA(2)alpha may offer an efficient target for treatment of ALS.