Neuropharmacology
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Comparative Study
AS1069562, the (+)-isomer of indeloxazine, but not duloxetine has a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy.
AS1069562 is the (+)-isomer of indeloxazine, which had been clinically used as a cerebral activator for the treatment of cerebrovascular diseases with serotonin and norepinephrine reuptake inhibition (SNRI) and neuroprotection. Here, we compared the analgesic effects of repeated treatment with AS1069562 and duloxetine, a selective SNRI, on pain-related behavior in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Further, we also evaluated the effects on the expression of neurotrophic factors and nerve conduction velocity. ⋯ The results of this study indicate that the analgesic effect of repeated dosing of AS1069562 but not duloxetine is persistent even after a 1-week drug discontinuation in STZ-induced diabetic rats. Restoration of neurotrophic factors may be involved in the curative-like pharmacological effect of this agent. Thus, AS1069562 may potentially offer a better treatment option for patients with painful diabetic neuropathy than duloxetine via different mechanisms.
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Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs decrease L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID); the implication of dopamine neurotransmission is not documented in this anti-LID activity. Therefore, we evaluated changes of dopamine receptors, their associated signaling proteins and neuropeptides mRNA, in normal control monkeys, in saline-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in L-DOPA-treated MPTP monkeys, without or with an adjunct treatment to reduce the development of LID: 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist. All de novo treatments were administered for 1 month and the animals were sacrificed thereafter. ⋯ Striatal [(3)H]raclopride specific binding correlated positively with D2 receptor mRNA levels of all MPTP-lesioned monkeys. Striatal preproenkephalin/preprodynorphin mRNA levels and phosphorylated ERK1/2 and Akt/GSK3β levels increased only in L-DOPA-treated MPTP monkeys as compared to controls, saline treated-MPTP and l-DOPA + MPEP treated MPTP monkeys. Hence, reduction of development of LID with MPEP was associated with changes in D2 receptors, their associated signaling proteins and neuropeptides.
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Angiotensin (Ang) II exaggerates cerebral injury in ischemic damage. Angiotensin-converting enzyme type 2 (ACE2) converts Ang II into Ang (1-7) and thus, may protect against the effects of Ang II. We hypothesized that neuronal ACE2 over-expression decreases ischemic stroke in mice with Ang II overproduction. ⋯ Two days after surgery, brain samples were collected for various analyses. Results showed: 1) When compared to chronically hypertensive RA mice, SARA mice had lower basal MAP, less MCAO-induced infarct volume, and increased CBF, neurological function and cerebral microvascular density in the peri-infarct area; 2) These changes in SARA mice were not altered after MAP "clamping", but partially reversed by brain infusion of A-779; 3) Ang (1-7)/Ang II ratio, angiogenic factors, endothelial nitric oxide synthase (eNOS) expression and nitric oxide production were increased, whereas, NADPH oxidase subunits and reactive oxygen species were decreased in the brain of SARA mice. ACE2 protects brain from ischemic injury via the regulation of NADPH oxidase/eNOS pathways by changing Ang (1-7)/Ang II ratio, independently of MAP changes.
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Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. ⋯ Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level.
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Chemokines are associated with both inflammatory and immune responses and play an important role in the pathophysiological process associated with neuropathic pain following peripheral nerve injury. Here, we investigated the involvement of peripheral keratinocyte-derived chemokine (KC) in the pathogenesis of neuropathic pain induced by the partial ligation of the sciatic nerve (PLSN) in mice. PLSN increased KC levels and its mRNA in both the sciatic nerve and spinal cord when compared with sham-operated mice. ⋯ We also demonstrated an increased level of cytokines (IL-1β, IL-6, and MCP-1, but not TNF-α) after i.n. injection of KC in the mouse sciatic nerve. Together, these findings suggest a role for KC in the development of neuropathic pain in mice by attracting neutrophils to the injured site and increasing the production of proinflammatory mediators. Therefore, strategies to inhibit the action or the release of this chemokine could constitute a therapeutic tool for the management of neuropathic pain in humans.