August 13, 2020
The neurons in the adult central nervous system (CNS) fail to regenerate axons after injury, which accounts in part for the poor functional recovery in patients with traumatic and neurodegenerative diseases (1).
The failure of axon regeneration is attributable to a growth-inhibiting environment involving myelin-associated inhibitors (Nogo-A, myelin-associated glycoprotein, and oligodendrocyte/myelin glycoprotein) and glial scar at the injury site.However, neutralizing and/or removing such inhibitory factors are insufficient to promote long-distance axon regeneration (1).
In this study, in an effort to discover new pharmacological modalities to aid in axon regeneration, we employed phenotypic cell-based screens that allow visual assessment and quantitative measurement of neurite outgrowth in vitro. The phenotypic screening campaign and chemical modification efforts led to identification of compound 7p that enhances neurite outgrowth in cultured primary neurons derived from the hippocampus, cerebral cortex, and retina and that induces optic nerve regeneration in an animal model of optic nerve injury. Although it needs to be determined how the compound stimulates axon growth in vivo, our results should provide further insight into the treatment strategies for clinical conditions associated with a loss of axon.
Another report using phenotypic cell-based screen of chemical libraries and structure-activity-guided optimization resulted in the identification of compound 7p which promotes neurite outgrowth of cultured primary neurons derived from the hippocampus, cerebral cortex, and retina. in an animal model of optic nerve injury, compound 7p was shown to induce growth of gap-43 positive axons, indicating that the in vitro neurite outgrowth activity of compound 7p translates into stimulation of axon regeneration in vivo.further optimization of compound 7p and elucidation of the mechanisms by which it elicits axon regeneration in vivo will provide a rational basis for future efforts to enhance treatment strategies.
Compound 7p (2-[(2-methoxyphenyl)[(4-methyl phenyl) sulfonyl] amino]-N-(4-methoxy-3-pyridinyl) acetamide) showed the highest activity against cervical cancer cells. In a nude mouse xenograft model inoculated with HeLa cells, 7p showed dose-dependent inhibition of cervical tumour growth. Histopathological examination of excised tumour-bearing tissues showed that 7p improved the microstructure in a dose-dependent manner. Compound 7p also increased the proportions of HeLa cells in G0/G1 and S-phase and significantly decreased that of G2/M-phase. The effects of 7p on C-caspase-3, C-caspase-9, Bcl-2 and Bax expression in HeLa cells were also determined.
Compound 7p was developed as one in series of compounds with the aim of identifying dual-acting thromboxane receptor antagonist/synthase inhibitors. In fact compound 7p shows selectivity for prostaglandin I2 synthase (PTGIS, CYP8A1) over thromboxane synthase (CYP5A1).