Amelioration of caspase 3,7 activity by SP01 in human primary neurons exposed to HIV
Amol Shah1, Gursharan Chana1,2, Ginger R Lucero1, Eliezer Masliah3, Cristian L Achim1, Laurent Lecanu4, Vassilios Papadopoulos4, Janet Greeson5, Ian P Everall1,2
1Department of Psychiatry, HIV Neurobehavioral Research Center, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA; 2Department of Psychiatry, The University of Melbourne, Royal Melbourne Hospital, VIC, 3050, Australia; 3Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA; 4The Research Institute of the McGill University Health Centre and Department of Medicine, McGill University, Montreal QC, Canada; 5Samaritan Pharmaceuticals, Las Vegas, Nevada
Abstract: Despite development of antiretroviral therapy (ARV) HIV associated neurocognitive disorder (HAND) continues to be a significant cause of morbidity. As ARVs are not entirely effective against HAND, there is significant motivation to discover novel therapies that are targeted towards the treatment of HAND. A novel formulation of procaine hydrochloride, SP01, is one potential molecule which has shown promise. Phase I clinical trials have found SP01 treatment to significantly increase CD4 cell counts and quality of life parameters in HIV infected patients. To assess SP01’s potential use for HAND we utilized an in vitro human primary neuron culture model and conducted co-exposure experiments with gp120 ([BaL] 300 pg/mL) or HIV (BaL) 500 pg/mL) with or without SP01 (10 µM) and measured the activity of the pro-apoptotic caspases 3/7 using a quantitative luminescence assay. Both gp120 and HIV resulted insignificant increase in caspase 3/7 activity from controls (P < 0.05). This effect was ameliorated with co-exposure with SP01 (P < 0.05). The reduction in activity of caspases 3 and 7, which are well known to be cellular triggers for apoptosis, signifies that SP01 is likely to have neuroprotective effects against HIV induced neurodegeneration via inhibition of pro-apoptotic cascades. Given its success in clinical trials and in vitro experiments, SP01 seems to be a legitimate contender in the fight against HAND.
Keywords: HIV, SP01, neurotoxicity, caspase, HAND, neuroprotection
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