Abstract
The antiapoptotic, neuroprotective compound P7C3-A20 reduces neurological deficits when administered to murine in-vivo models of traumatic brain injury. P7C3-A20 is thought to exert its activity through small-molecule activation of the enzyme nicotinamide phosphoribosyltransferase. This enzyme converts nicotinamide to nicotinamide mononucleotide, the precursor to nicotinamide adenine dinucleotide synthesis. Alterations to this bioenergetic pathway have been shown to induce Wallerian degeneration (WD) of the distal neurite following injury. This study aimed to establish whether P7C3-A20, through induction of nicotinamide phosphoribosyltransferase activity, would affect the rate of WD. The model systems used were dissociated primary cortical neurons, dissociated superior cervical ganglion neurons and superior cervical ganglion explants. P7C3-A20 failed to show any protection against WD induced by neurite transection or vincristine administration. Furthermore, there was a concentration-dependent neurotoxicity. These findings are important in understanding the mechanism by which P7C3-A20 mediates its effects – a key step before moving to human clinical trials.
Highlights
In 2010 the antiapoptotic, neuroprotective aminopropyl carbazole agent P7C3 was discovered using a novel in-vivo screening approach [1]
NAM is converted to nicotinic acid (NA) by nicotinamidase, and NA is converted to Nicotinic acid mononucleotide (NaMN) by nicotinic acid phosphoribosyltransferase (NaPRT)
To select an appropriate concentration of P7C3-A20 to test in Wallerian degeneration (WD), we first assessed for toxicity over a wide concentration range (50 nm to 10 μM) in a variety of neuronal cell types (Fig. 2)
Summary
In 2010 the antiapoptotic, neuroprotective aminopropyl carbazole agent P7C3 was discovered using a novel in-vivo screening approach [1]. P7C3, and one of its more active fluorinated enantiomers P7C3-A20, has shown promise as a therapeutic agent in a number of conditions that have been associated with WD. It was capable of blocking 1-methyl-4phenyl-1,2,3,4-tetrahydropyridine-induced death of dopaminergic substantia nigra cells in an adult mouse model of Parkinson’s disease [2]. The potential for benefit of P7C3 derivatives in traumatic brain injury (TBI) was indicated by the findings that the analogue P7C3-S243, prevented retinal ganglion cell loss following experimental blast injury in mice [4] This was followed by a demonstration that P7C3-S243
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