Hirsutine, an indole alkaloid of Uncaria rhynchophylla, inhibits inflammation-mediated neurotoxicity and microglial activation

Abstract

Chronic microglial activation endangers neuronal survival through the release of various pro-inflammatory and neurotoxic factors. As such, negative regulators of microglial activation have been considered as potential therapeutic candidates to reduce the risk of neurodegeneration associated with inflammation. Uncaria rhynchophylla (U. rhynchophylla) is a traditional oriental herb that has been used for treatment of disorders of the cardiovascular and central nervous systems. Hirsutine (HS), one of the major indole alkaloids of U. rhynchophylla, has demonstrated neuroprotective potential. The aim of the present study was to examine the efficacy of HS in the repression of inflammation-induced neurotoxicity and microglial cell activation. In organotypic hippocampal slice cultures, HS blocked lipopolysaccharide (LPS)-related hippocampal cell death and production of nitric oxide (NO), prostaglandin (PG) E2 and interleukin-1β. HS was demonstrated to effectively inhibit LPS-induced NO release from cultured rat brain microglia. The compound reduced the LPS-stimulated production of PGE2 and intracellular reactive oxygen species. HS significantly decreased LPS-induced phosphorylation of the mitogen-activated protein kinases and Akt signaling proteins. In conclusion, HS reduces the production of various neurotoxic factors in activated microglial cells and possesses neuroprotective activity in a model of inflammation-induced neurotoxicity.

Prevention of inflammation‐mediated neurotoxicity by butylidenephthalide and its role in microglial activation

“…We have recently shown that LPS at 10 mg ml À1 prominently reduced immunoreactivity of NeuN, a neuronal-specific marker, together with elevated propidium iodide (PI) fluorescence in OHSCs. 28 In the same experimental condition, the immunoreactivity for Iba1, a microglia-specific marker, did not seem to be reduced after the LPS insult (data not shown). After stimulation with LPS for 72 h, the culture medium was collected and subjected to nitrite and cytokine assays and was subsequently replaced with fresh serum-free medium containing PI.…”

“…The concentration of LPS required for neurotoxicity in tissue cultures was higher than that used in primary microglial cultures. We have recently shown that LPS at 10 µg ml −1 prominently reduced immunoreactivity of NeuN, a neuronal‐specific marker, together with elevated propidium iodide (PI) fluorescence in OHSCs . In the same experimental condition, the immunoreactivity for Iba1, a microglia‐specific marker, did not seem to be reduced after the LPS insult (data not shown).…”

Medicinal uses, phytochemistry and pharmacology of the genus Uncaria

“…In vitro investigations have shown that Uncaria plants ameliorate amyloid-β-induced neuronal death, methamphetamine-induced rat cortical neurons death, glutamate-induced PC12 cell death and LPS-induced hippocampal cell death, etc (Jung et al, 2013;Kawakami et al, 2011;Mo et al, 2006;Xian et al, 2012b). In vivo experiments have revealed that Uncaria plants improve learning and memory impairments and dementia-like behaviors in various animal models (Fujiwara et al, 2011;Xian et al, 2011;Xian et al, 2014a).…”

An integrated strategy for the systematic characterization and discovery of new indole alkaloids from Uncaria rhynchophylla by UHPLC/DAD/LTQ-Orbitrap-MS

“…Our recent work focusing on an anti-inflammatory extract of UR isolated 11 oleanane and ursane triterpenic acids, three of which showed weak inhibitory effects on LPS-induced NO production in RAW264.7 cells [22]. The potential neuroprotective function of UR may be due to indole alkaloids [23][24][25][26]. Indole alkaloids are used as biomarkers for the quality control of Gou-Teng [27,28].…”