European journal of pharmacology
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The neuroprotective effect of DBZIM, a novel imidazolium compound, has previously been documented to slow down neurodegeneration in a mouse model of Parkinson's disease. In this study, we conducted behavioural studies and further investigated the neuroprotection in a rat Parkinsonian model induced by 6-hydroxydopamine (6-OHDA). DBZIM was found to significantly reduce the 6-OHDA-induced asymmetrical rotation and preferential usage of contralateral forelimbs. ⋯ In addition, DBZIM attenuated the activation of astrocytes and microglia. This suggests that anti-inflammation may be an additional mechanism underlying the DBZIM-mediated neuroprotection. These findings warrant further investigation of DBZIM as a promising and potent agent for the future treatment of Parkinson's disease.
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Ergotamine has been used in clinical practice for the acute treatment of migraine for over 90 years. So far, it is known that ergotamine interacts with diverse receptors (including α1/2-adrenoceptors, 5-HT1, 5-HT2 and D2-like receptors) and that produces increases in mean blood pressure which are significantly blocked by yohimbine, a classical α2-adrenoceptor antagonist with a moderate affinity for α1-adrenoceptors. Since α1/2-adrenoceptors mediate vasopressor and vasoconstrictor responses in the cardiovascular system, this study was designed to identify the α-adrenoceptor subtypes (α1A, α1B, α1D, α2A, α2B and α2C) involved in ergotamine-induced vasopressor responses in pithed rats. ⋯ Then, the vasopressor responses to intravenous (i.v.) bolus injections of ergotamine were determined after administration of vehicle or several α1⧸2-adrenoceptor antagonists. I.v. administration of the antagonists prazosin (α1, 0.1-30 µg/kg), rauwolscine (α2, 0.3-300 µg/kg), prazosin (0.1 µg/kg) plus rauwolscine (0.3 µg/kg), 5-methylurapidil (α1A, 100 and 300 µg/kg), L-765,314 (α1B, 100 and 300 µg/kg), BMY 7378 (α1D, 100 and 300 µg/kg), BRL44408 (α2A, 300 and 1000 µg/kg) and JP-1302 (α2C, 300 µg/kg), significantly blocked the vasopressor responses to ergotamine, whereas imiloxan (α2B, 1000 and 3000 µg/kg), JP-1302 (100 µg/kg) or the corresponding vehicles (saline 0.9%, propylene glycol 20% or dimethyl sulfoxide 10%; 1ml/kg) failed to modify the responses to ergotamine. The above results suggest that the vasopressor responses to ergotamine in pithed rats are mainly mediated by α1A-, α1B-, α1D-, α2A- and α2C-adrenoceptors and may explain its adverse/therapeutic effects.
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Valproate is widely used for migraine treatments, although precise mechanisms of its anticephalgic action are poorly understood. Migraine attacks are thought to occur due to trigemino-vascular system activation, which in turn, stimulates nociceptive transmission in trigemino-thalamo-cortical pathway. The ventroposteromedial (VPM) nucleus of the thalamus is considered to play a prominent role in neurobiology of headaches by serving as the highest subcortical relay for conveying nociceptive information from intra- and extra-cranial structures to the cortex. ⋯ Intravenous administration of valproate produced the dose-dependent suppression of both the ongoing activity of the thalamic VPM neurons and their responses to electrical stimulation of the dura mater. This effect was fast-developing (within 5 min) and short-lasting (no longer than 30 min). These data suggest that intravenous administration of valproate could produce a reduction of the thalamo-cortical nociceptive transmission associated with trigemino-vascular activation.
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SMND-309 is a novel derivative of salvianolic acid B, and has shown protective effects against rat cortical neuron damage in vitro and in vivo. However the molecular mechanisms through which SMND-309 affords this protection are unclear. The present study aimed to investigate the mechanisms associated with the protective activities of SMND-309 in a cerebral ischemia and reperfusion injury rat model. ⋯ SMND-309 mitigated the effects of ischemia and reperfusion injury on brain by decreasing the infract volume, improving neurological function, increasing the survival of neurons and promoting angiogenesis by increasing the levels of erythropoietin (EPO), erythropoietin receptor (EPOR), phosphorylated JAK2 (P-JAK2), phosphorylated STAT3 (P-STAT3), VEGF and VEGF receptor 2 (Flk-1) in the brain. Our results suggest that SMND-309 provides significant neuroprotective effects against cerebral ischemia and reperfusion injury. The mechanisms of this protection may be attributed to the increased VEGF expression occurring from the JAK2/STAT3 pathway, activated by the increased EPO/EPOR expression in the brain.
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Dexketoprofen and tramadol, alone or in combination, were evaluated after oral or intra-articular administration on knee osteoarthritis nociception induced by intra-articular (i.ar.) monosodium iodoacetate (MIA, 1 mg/25 µl) in the rat right knee while the left knee received saline (25 µl). Seven days after MIA treatment, dexketoprofen, tramadol, their combination or the vehicle were administered. Nociception was evaluated as alteration in hind limb weight distribution with Incapacitance tester at different time-points after drug administration. ⋯ This effect was significantly reduced by naloxone (10 μg/25 μl, i.ar.) co-administered with both compounds. The intra-articular administration of both drugs at 10 µg/25 µl in the contralateral control knee joint provoked a marked synergistic antinociceptive effect indicating significant systemic diffusion through synovial membrane. The oral or intra-articular combination of dexketoprofen and tramadol produced additive or synergistic antinociceptive effects, respectively, in the model of MIA-induced osteoarthritis in rats, that might allow to obtain therapeutic advantages with lower side effects.