The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jul 2005
A novel neurotrophic agent, T-817MA [1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate], attenuates amyloid-beta-induced neurotoxicity and promotes neurite outgrowth in rat cultured central nervous system neurons.
Progressive neuronal loss in Alzheimer's disease (AD) is considered to be a consequence of the neurotoxic properties of amyloid-beta peptides (A beta). T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate) was screened as a candidate therapeutic agent for the treatment of AD based on its neuroprotective potency against A beta-induced neurotoxicity and its effect of enhancing axonal regeneration in the sciatic nerve axotomy model. The neuroprotective effect of T-817MA against A beta(1-42) or oxidative stress-induced neurotoxicity was assessed using a coculture of rat cortical neurons with glia. ⋯ T-817MA also increased the growth-associated protein 43 content in the reaggregation culture of cortical neurons. These findings suggest that T-817MA exerts neuroprotective effect and promotes neurite outgrowth in rat primary cultured neurons. Based on these neurotrophic features, T-817MA may have a potential for disease modification and be useful for patients with neurodegenerative diseases, such as AD.
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J. Pharmacol. Exp. Ther. · Jul 2005
Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice.
The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel localized on a subset of primary sensory neurons and can be activated by a wide range of stimuli. The present study investigated the role of this receptor in chronic arthritis evoked by complete Freund's adjuvant (CFA) using TRPV1 receptor gene-deleted (TRPV1-/-) mice and wild-type counterparts (TRPV1+/+). In TRPV1+/+ mice, CFA injected intraplantarly into the left hindpaw and the root of the tail induced swelling of the injected and contralateral paws up to 130 and 28%, respectively, measured by plethysmometry throughout 18 days. ⋯ The effect of indomethacin was markedly smaller in knockouts. In TRPV1+/+ animals, HOE-140, but not desArgHOE-140, inhibited arthritis, whereas in TRPV1-/- mice, HOE-140 produced limited effect. Thus, whereas bradykinin and lipoxygenase products seem to act exclusively via TRPV1 activation, prostanoids do not, or at least only partially, to enhance murine experimental arthritis and related hyperalgesia.
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J. Pharmacol. Exp. Ther. · Jul 2005
D1 dopamine receptors modulate deltaFosB induction in rat striatum after intermittent morphine administration.
Induction of the transcription factor deltaFosB was studied to examine neurochemical adaptations produced by repeated opiate administration. The mechanism of this induction was also investigated. The 35- to 37-kDa isoforms of deltaFosB, also referred to as the chronic Fras, were measured in the nucleus accumbens, caudate putamen, and frontal cortex of male Sprague-Dawley rats after either an acute injection of morphine or an escalating dosing schedule of morphine for 10 days. ⋯ Heroin administered twice daily for 10 days by an intermittent escalating dose schedule also induced deltaFosB in the caudate putamen, but not in the nucleus accumbens or frontal cortex. Daily pretreatment with the selective D1-like dopamine receptor antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] significantly blocked morphine-induced deltaFosB induction in the nucleus accumbens and caudate putamen, but not in the frontal cortex. These results demonstrate that morphine-induced deltaFosB up-regulation in the striatum, but not in the frontal cortex, is modulated by D1 dopamine receptors, suggesting that the mechanisms involved in the up-regulation of these chronic Fras by morphine is brain region-specific.
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J. Pharmacol. Exp. Ther. · Jul 2005
Prolonged positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/Dlg/ZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices.
Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan 10-one], a positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. ⋯ Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.
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J. Pharmacol. Exp. Ther. · Jul 2005
A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats.
The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. ⋯ A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.