Brain research
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Comparative Study
Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation.
The Alzheimer's disease Abeta peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Abeta and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-beta (Abeta), the fibrillar prion peptides PrP106-126 and PrP178-193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. ⋯ This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18-146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders.
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Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). ⋯ Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats.
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Serotonin type 2 (5-HT(2)) receptors reportedly inhibit neuropathic pain in the spinal cord, but little is known about how spinal 5-HT(2) receptors might act against such abnormal sensitivity. We examined whether the cholinergic and tachykinin systems were involved in the antiallodynic effect of intrathecally administered 5-HT(2) receptor agonists in rats with nerve injury. Allodynia was produced by tight ligation of the left L5 and L6 spinal nerves, and determined by applying von Frey hairs to the left hindpaw. ⋯ Antiallodynic effects of 5-HT(2) receptor agonists were attenuated by the 5-HT(2A) receptor antagonist ketanserin (30 micro g), but not by the 5-HT(2C) receptor antagonist RS-102221 (40 micro g). Muscarinic receptor antagonists (30 micro g each), the choline uptake blocker (10 micro g), and the NK(1) receptor antagonist (30 micro g) also inhibited the antiallodynic effects of 5-HT(2) receptor agonists. Antiallodynic effects of intrathecally administered 5-HT(2) receptor agonists may be mediated by spinal release of acetylcholine induced via 5-HT(2A) and NK(1) receptors.
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Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce antinociception. However, the mechanisms of the action of cholinergic agents in the spinal cord are not fully understood. Activation of spinal muscarinic receptors evokes gamma-aminobutyric acid (GABA) release, which reduces the glutamatergic synaptic input to dorsal horn neurons through GABA(B) receptors. ⋯ Furthermore, the antiallodynic effect of intrathecal neostigmine and muscarine was largely eliminated by CGP55845 in diabetic rats. These data suggest that the GABA(B) receptors in the spinal cord mediate both the antinociceptive and antiallodynic actions of intrathecal muscarine or neostigmine in normal rats and in a rat model of diabetic neuropathic pain. This study provides new functional evidence that activation of spinal GABA(B) receptors is one of the important mechanisms underlying the antinociceptive action of intrathecal cholinergic agents.
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Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids. Although LF and the LF receptor have been identified in the central nervous system (CNS), the physiological role of LF remains unknown. We found that bovine milk-derived LF (BLF) reduces nociception in various pain models, as shown by the formalin test, hot plate test, and acetic acid writhing test in rats. ⋯ The antinociceptive effects of BLF were blocked by naloxone treatment, even though prostaglandin E(2) (PGE(2)) production in the ascites fluid that accumulated during the writhing test was not affected by BLF. Intrathecal (i.t.) application of BLF caused marked antinociceptive effects that were reversed by co-administration of a specific mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-NH(2) (CTOP), or by naloxone during the formalin test. We conclude that LF possesses mu-opioid receptor-mediated antinociceptive activity in the spinal cord.