British journal of pharmacology
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N-arachidonoyl dopamine (NADA) has complex effects on nociception mediated via cannabinoid CB(1) receptors and the transient receptor potential vanilloid receptor 1 (TRPV1). Anandamide, the prototypic CB(1)/TRPV1 agonist, also inhibits T-type voltage-gated calcium channel currents (I(Ca)). These channels are expressed by many excitable cells, including neurons involved in pain detection and processing. We sought to determine whether NADA and the prototypic arachidonoyl amino acid, N-arachidonoyl glycine (NAGly) modulate T-type I(Ca) ⋯ N-arachidonoyl dopamine and NAGly increase the steady-state inactivation of Ca(V)3 channels, reducing the number of channels available to open during depolarization. These effects occur at NADA concentrations at or below to those affecting CB(1) and TRPV1 receptors. Together with anandamide, the arachidonoyl neurotransmitter amides, NADA and NAGly, represent a new family of endogenous T-type I(Ca) modulators.
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Protein kinase (PK) A and the epsilon isoform of PKC (PKCepsilon) are involved in the development of hypernociception (increased sensitivity to noxious or innocuous stimuli) in several animal models of acute and persistent inflammatory pain. The present study evaluated the contribution of PKA and PKCepsilon to the development of prostaglandin E(2) (PGE(2))-induced mechanical hypernociception. ⋯ Taken together, these findings are consistent with the suggestion that PKA activates PKCepsilon, which is a novel mechanism of interaction between these kinases during the development of PGE(2)-induced mechanical hypernociception.
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We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP). ⋯ Chronic CHF5074 treatment reduced brain beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease.
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Traditionally, the stem and root bark of Ulmus davidiana var. japonica (Ulmaceae) have been known to be anti-inflammatory in Korea. Anti-inflammatory effects of torilin, isolated from this plant and the underlying mechanisms were examined by using lipopolysaccharide (LPS)-stimulated microglial BV2 cells. ⋯ This study indicates that torilin inhibited LPS-induced iNOS, COX-2 and IL-1beta via down-regulation of ERK1/2, p38 MAPK, NF-kappaB and CREB and suggests that torilin has a potential as an anti-inflammatory drug candidate.