Journal of pharmacological sciences
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Pathological hallmarks of Alzheimer's disease (AD) include senile plaques, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaques are composed of amyloid-β (Aβ) and are surrounded by microglia, a primary immune effector cell in the central nervous system. NFTs are formed by the intraneuronal accumulation of hyperphosphorylated tau, and progressive synaptic and neuronal losses closely correlate with cognitive deficits in AD. ⋯ Although details of the interaction between AD pathologies remain unclear, experimental evidences to discuss this issue have been accumulated. In this paper, we review and discuss recent findings that link the AD pathologies to each other. Further studies on the interaction between pathologies induced in AD brain may contribute to provide deep insight into the pathogenesis of AD and to develop novel therapeutic, prophylactic, and early diagnostic strategies for AD.
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Peripheral neuropathic pain is a serious side effect of paclitaxel treatment. However, the mechanism of this paclitaxel-induced neuropathic pain is unknown. In this study, we investigated the effects of paclitaxel on the voltage-dependent calcium channel (VDCC) current in rat dorsal root ganglion (DRG) neurons using the whole-cell patch clamp technique. ⋯ Immunohistochemistry showed that paclitaxel treatment increased Ca(v)α₂δ-1 protein expression in DRG neurons. Thus, paclitaxel treatment increases the VDCC current in small- and medium-diameter DRG neurons and upregulates Ca(v)α₂δ-1. The antihyperalgesic action of gabapentin may be due to inhibition of paclitaxel-induced increases in the VDCC current in DRG neurons.
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We studied the antiallodynic effect of gabapentin (GBP) in the mouse model of neuropathic pain, aiming at clarifying the underlying mechanism. The L5 spinal nerve ligation induced tactile allodynia, an increase of CD11b expression, and an increase in the protein expression level of the voltage-dependent Ca(2+) channel α(2)/δ-1 subunit in the spinal dorsal horn on the injured side. The chronic intrathecal administration of GBP (100 µg/body per day) as well as ω-conotoxin MVIIA, an N-type Ca(2+)-channel blocker, completely suppressed allodynia, but did not attenuate the CD11b expression. ⋯ GBP suppressed the elevation of the protein level of the α(2)/δ-1 subunit in the spinal dorsal horn, although it did not affect its mRNA level in the L5 DRG. These results suggest that GBP inhibits the development of allodynia by suppressing the up-regulation of N-type Ca(2+) channels, through normalization of the protein level of the α(2)/δ-1 subunit at the primary afferent nerve terminal via the inhibition of its anterograde transport. In addition, we propose that the nerve injury enhances the expression level of α(2)/δ-1 in the downstream of the activation of microglia.
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Syzygium cumini (SC) is well known for its anti-diabetic potential, but the mechanism underlying its amelioration of type 2 diabetes is still elusive. Therefore, for the first time, we investigated whether SC aqueous seed extract (100, 200, or 400 mg/kg) exerts any beneficial effects on insulin resistance (IR), serum lipid profile, antioxidant status, and/or pancreatic β-cell damage in high-fat diet / streptozotocin-induced (HFD-STZ) diabetic rats. Wistar albino rats were fed with HFD (55% of calories as fat) during the experiment to induce IR and on the 10th day were injected with STZ (40 mg/kg, i.p.) to develop type 2 diabetes. ⋯ These alterations reverted to near-normal levels after treatment with SC at 400 mg/kg. Moreover, hepatic tissue demonstrated increased PPARγ and PPARα protein expressions. Thus, our study demonstrated the beneficial effect of SC seed extract on IR and β-cell dysfunction in HFD-STZ-induced type 2 diabetic rats.
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Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Amitriptyline has widely been used in patients with painful neuropathy. ⋯ Repeated administration of amitriptyline (5 and 10 mg/kg, p.o., once a day) reduced the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia and reversed the oxaliplatin-induced increase in the expression of NR2B protein and mRNA in rat spinal cord. These results suggest that amitriptyline is useful for the treatment of oxaliplatin-induced neuropathy clinically.