DSpace community: 藥理學科暨研究所

Synthesis and Antiplatelet Activity of 9-Benzyl-3-Hydroxymethylcarbazoles

Wed, 23 Sep 2009 08:48:53 GMT

title: Synthesis and Antiplatelet Activity of 9-Benzyl-3-Hydroxymethylcarbazoles

Hypoxia-Induced Inos Expression in Microglia Is Regulated by the P13- Kinase/Akt/Mtor Signaling Pathway and Activation of Hypoxia Inducible Factor-1 Alpha

Wed, 23 Sep 2009 08:46:20 GMT

title: Hypoxia-Induced Inos Expression in Microglia Is Regulated by the P13- Kinase/Akt/Mtor Signaling Pathway and Activation of Hypoxia Inducible Factor-1 Alpha abstract: Exposure to hypoxia induced microglia activation and animal studies have shown that neuronal cell death is correlated with microglial activation following cerebral ischemia. Thus , it is likely that toxic inflammatory mediators produced by activated microglia under hypoxic conditions may exacerbate neuronal injury following cerebral ischemia. The hypoxia- inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O-2 level, which is regulated by many physiological functions. However, the role of HIF-1 in microglia activation underhypoxiahas not yet been defined. In the current work, we investigate the signaling pathways of HIF-1 alpha involved in the regulation of hypoxia-induced overexpression of inducible NO synthase ( iNOS) in microglia. Exposure of primary rat microglial cultures as well as established microglial cell line BV-2 to hypoxia induced the expression of iNOS, indicating that hypoxia could lead to the inflammatory activation of microglia. iNOS induction was accompanied with NO production. Moreover , the molecular analysis of these events indicated that iNOS expression was regulated by the phosphatidylinositol 3-kinase (PI3-kinase)/AKT/ mammalian target of rapamycin (mTOR) signaling pathway and activation of hypoxia inducible factor-1 alpha (HIF-1 alpha). Thus, during cerebral ischemia, hypoxia may not only directly damage neurons, but also promote neuronal injury indirectly via microglia activation. In this study, we demonstrated that hypoxia induced iNOS expression by regulation of HIF-1 alpha in microglia. (c) 2006 Elsevier Inc. All rights reserved.

Mechanisms of the Antinociceptive Action of Gabapentin

Wed, 23 Sep 2009 08:45:09 GMT

title: Mechanisms of the Antinociceptive Action of Gabapentin abstract: Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABAB receptors consisting of GABAB1a and GABAB2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K+ channels, activating hyperpolarization-activated cation channels, and modulating Ca2+ current by selectively binding to the specific binding site of [3H]gabapentin, the α2δ subunit of voltage- dependent Ca2+ channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the α2δsubunit of spinal N-type Ca2+ channels is very likely the analgesic action target of gabapentin.

The Antiallodynic Action Target of Intrathecal Gabapentin: Ca2+ Channels, K-Atp Channels or N-Methyl-D-Aspartic Acid Receptors?

Wed, 23 Sep 2009 08:44:05 GMT

title: The Antiallodynic Action Target of Intrathecal Gabapentin: Ca2+ Channels, K-Atp Channels or N-Methyl-D-Aspartic Acid Receptors? abstract: Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)sensitive K+ (K-ATP) channels, N-methyl-D-aspartic acid (NMDA) receptors, and Ca2 + channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mu g) was not affected by intrathecal pretreatment with antagonists of K-ATP channels, NMDA receptors or gamma-aminobutyric acid (GABA), receptors . K-ATP channel openers and GABA, receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega -conotoxin GVIA, 0. 1-3 mu g), but not of P/Q-type (omega-agatoxin IVA), L -type (verapamil, diltiazem or nimodipine), or T-type (mibefradil) , attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L- type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K-ATP channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.