BackgroundWe recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.MethodsIn contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. We exploited this fact by comparing rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels.ResultsCompared to WT rats, HIP rats show i) reduced exploratory drive, ii) impaired recognition memory and iii) no ability to improve the performance on the rotarod. The development of neurological deficits is associated with amylin accumulation in the brain. The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates is almost double in HIP rats compared with WT littermates (P < 0.05). Large amylin deposits (>50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin alters the brain structure at the molecular level. Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which are clustering in areas positive for amylin infiltration. Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that amylin deposition in the brain induces a neuroinflammatory response.ConclusionsHyperamylinemia promotes accumulation of oligomerized amylin in the brain leading to neurological deficits through an oligomerized amylin-mediated inflammatory response. Additional studies are needed to determine whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline.
The G-protein activated, inward-rectifying potassium (K + ) channels, "GIRKs", are a family of ion channels (K ir 3.1-K ir 3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo-and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.
Hypocretin/orexin (Hcrt) neurons in the lateral hypothalamus project throughout the brain, including to the hippocampus, where Hcrt receptors are widely expressed. Hcrt neurons activate these targets to orchestrate global arousal state, wake-sleep architecture, energy homeostasis, stress adaptation, and reward behaviors. Hcrt has recently been implicated in cognitive functions and social interaction. Here, we tested the hypothesis that Hcrt neurons are critical to social interaction, particularly social memory, using neurobehavioral assessment and electrophysiological approaches. The validated “two-enclosure homecage test” devices and procedure were used to test sociability, preference for social novelty (social novelty), and recognition memory. A conventional direct contact social test was conducted to corroborate the findings. We found that adult orexin/ataxin-3 transgenic mice (AT, in which Hcrt neurons degenerate by 3 months of age) displayed normal sociability and social novelty with respect to wildtype (WT) littermates. However, AT mice displayed deficits in long-term social memory. Nasal administration of exogenous Hcrt-1 restored social memory to an extent in AT mice. Hippocampal slices taken from AT mice exhibited decreases in degree of paired-pulse facilitation (PPF) and magnitude of long-term potentiation (LTP), despite displaying normal basal synaptic neurotransmission in the CA1 area compared to WT hippocampal slices. AT hippocampi had lower levels of phosphorylated cyclic AMP-response element binding protein (pCREB), an activity-dependent transcription factor important for synaptic plasticity and long-term memory storage. Our studies demonstrate that Hcrt neurons play an important role in the consolidation of social recognition memory, at least in part through enhancements of hippocampal synaptic plasticity and CREB phosphorylation.
This article reviews material presented at the 2016 Scottsdale Headache Symposium. This presentation provided scientific results and rationale for the use of intranasal oxytocin for the treatment of migraine headache. Results from preclinical experiments are reviewed, including in vitro experiments demonstrating that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin. Results are also presented which demonstrate that nasal oxytocin inhibits responses of trigeminal nucleus caudalis neurons to noxious stimulation using either noxious facial shock or nitroglycerin infusion. These studies led to testing the analgesic effect of intranasal oxytocin in episodic migraineurs-studies which did not meet their primary endpoint of pain relief at 2 h, but which were highly informative and led to additional rat studies wherein inflammation was found to dramatically upregulate the number of oxytocin receptors available on trigeminal neurons. This importance of inflammation was supported by a series of in vivo rat behavioral studies, which demonstrated a clear craniofacial analgesic effect when a pre-existing inflammatory injury was present. The significance of inflammation was further solidified by a small single-dose clinical study, which showed analgesic efficacy that was substantially stronger in chronic migraine patients that had not taken an anti-inflammatory drug within 24 h of oxytocin dosing. A follow-on open label study examining effects of one month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs. This study led to a multicountry double blind, placebo controlled study studying whether, over 2 months of dosing, "as needed" dosing of intranasal oxytocin by chronic and high frequency migraineurs would reduce the frequency of their headaches compared to a 1-month baseline period. This study failed to meet its primary endpoint, due to an extraordinarily high placebo rate in the country of most of the patients (Chile), but was also highly informative, showing strong results in other countries and strong post hoc indications of efficacy. The results provide a strong argument for further development of intranasal oxytocin for migraine prophylaxis.
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