Abstract
CHR20 and CHR21 are a pair of stable diastereoisomers derived from genipin. These stereoisomers are activators of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). In the rat retinal ganglion (RGC-5) cell model these compounds are non-toxic. Treatment of RGC-5 with 750 μM of sodium nitroprusside (SNP) produces nitrosative stress. Both genipin derivatives, however, protect these cells against SNP-induced apoptic cell death, although CHR21 is significantly more potent than CHR20 in this regard. With Western blotting we showed that the observed neuroprotection is primarily due to the activation of protein kinase B (Akt)/eNOS and extracellular signal-regulated kinase (ERK1/2) signaling pathways. Therefore, LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or PD98059 (a MAPK-activating enzyme inhibitor) abrogated the protective effects of CHR20 and CHR21. Altogether, our results show that in our experimental setup neuroprotection by the diasteromeric pair is mediated through the PI3K/Akt/eNOS and ERK1/2 signaling pathways. Further studies are needed to establish the potential of these compounds to prevent ntric oxide (NO)-induced toxicity commonly seen in many neurodegenerative diseases.
Highlights
Nitric oxide (NO), a Janus-faced molecule with pleiotropic effects in different tissues, is physiologically produced through the L-arginine/NO synthase (NOS) pathway
It has been shown by other researchers that both ERK1/2 and phosphatidylinositol 3-kinase (PI3K) are involved in the induction of antioxidant expression, implying that the activations of Akt and ERK1/2 are required for the activation of nuclear factor-like 2 (Nrf2) followed by up-regulating mRNA expression of antioxidant in rat vascular smooth muscle cells [31]
Our data presented here show that CHR20/21 increase MTT activity of RGC-5 cells at a concentration of 30 μM and protect against pathological NO-induced cell apoptosis by the activations of total NOS (tNOS) and constructive NOS (cNOS), PI3K/Akt/endothelial nitric oxide synthase (eNOS) and ERK1/2 pathways in an RGC-5 cell model
Summary
Nitric oxide (NO), a Janus-faced molecule with pleiotropic effects in different tissues, is physiologically produced through the L-arginine/NO synthase (NOS) pathway. CHR21/20 were capable of increasing mRNA levels of two anti-oxidative proteins, namely GCLC and SOD1, to antagonize the effects of ROS [26] It has been shown by other researchers that both ERK1/2 and PI3K are involved in the induction of antioxidant expression, implying that the activations of Akt and ERK1/2 are required for the activation of nuclear factor-like 2 (Nrf2) followed by up-regulating mRNA expression of antioxidant in rat vascular smooth muscle cells [31]. PD98059 (a specific MAPK pathway inhibitor), and LY294002 (a specific PI3K inhibitor), respectively blocked the phosphorylation of Akt and ERK1/2 stimulated by CHR20/21 in RGC-5 cells, and attenuated the survival effects. It is likely that CHR20/21 stimulate eNOS via the activation of Akt
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