Protective efficacy of Hippophae rhamnoides L. extract exhibited in rat heart against hypobaric hypoxia is possibly mediated by configurations in JAK/STAT pathway

Hypoxia is a condition deprived of oxygen at tissue level, is known to be linked to oxidative stress and inflammatory cytokines. Hippophae rhamnoides L., commonly called Seabuckthorn, being rich in flavonoids, is reported to reduce oxidative stress. It is hypothesized that aqueous extract of H. rhamnoides relieves adverse changes in rat heart induced by continuous sub-acute hypobaric hypoxia. Exposure to continuous hypobaric hypoxia for seven days resulted in elevated levels of malondialdehyde, decrease in reduced glutathione, glutathione peroxidase and superoxide dismutase activities with concomitant increase in NFkB expression in rat heart. The levels of pro-inflammatory cytokines, TNFα and IL6 and TGFβ1, AKT and ERK were found to be decreased. The expression levels of JAK1 were reduced while STAT3 and STAT6 levels were found increased following hypoxia exposure. The treatment of rats with aqueous extract of H. rhamnoides significantly attenuated hypobaric hypoxia induced oxidative stress, increased TNFα and IL6 and deactivated NFҡB activity. H. rhamnoides treatment augmented expressions of JAK1, AKT and ERK proteins. Overall, results of this study indicate that the aqueous extract of Hippophae rhamnoides helps in inducing tolerance to rat heart at extreme altitude faster by optimizing tissue oxidative stress, preventing inflammatory response and configuring JAK1/ERK/AKT and STAT3/STAT6, at least to certain extent.

Protective role of alpha-ketoglutarate against massive doses of cyanide in rats.

Cyanide is a highly toxic cellular poison that requires immediate and aggressive treatments. Combination of sodium nitrite (SN) and sodium thiosulfate (STS) is the treatment of choice but oral treatment of alpha-ketoglutarate (A-KG) has also been shown to significantly antagonize cyanide poisoning in laboratory animals. This study reports the efficacy of various treatment regimens as : (i) repeated doses of A-KG after simultaneous treatment of A-KG and STS, (ii) repeated doses of A-KG after pre-treatment of SN, STS and A-KG, (iii) repeated doses of STS after pre-treatment of SN, STS and A-KG, and (iv) repeated doses of A-KG and STS after pretreatment of SN, STS and A-KG on mortality of female rats exposed to massive doses of potassium cyanide. A maximum of 40-folds protection was observed when A-KG at 1.0 g kg-1 after 2 hr and 0.5 g kg-1 after 4 hr was repeated following the pre-treatment of SN (0.025 g kg-1; subcutaneous; -45 min), STS (1.0 g kg-1; intraperitoneal; -15 min) and A-KG (2.0 g kg-1; oral; -10 min). Similar protection was also conferred by repeating 0.5 g kg-1 each of A-KG and STS 2 hr after pre-treatment of SN, STS and A-KG. Also, 38-folds protection after simultaneous administration of 2.0 g kg-1 A-KG and 1.0 g kg-1 STS, followed by 2.0 g kg-1 A-KG after 2 hr was noteworthy. The results indicate that repeated treatment of A-KG alone after simultaneous treatment of A-KG and STS or repeated treatment of A-KG alone or with STS after pre-treatment of A-KG, SN and STS have immense potential in challenging extremely high doses of cyanide as compared to the antidotes given once. The study has implications in the development of A-KG as an alternate treatment for cyanide poisoning.