Introduction: Epilepsy is a chronic neurological condition characterized by behavioral, molecular, and neurochemical alterations. Current antiepileptic drugs are associated with various adverse impacts. The main goal of the current study is to investigate the possible anticonvulsant effect of selenium nanoparticles (SeNPs) against pentylenetetrazole (PTZ)mediated epileptic seizures in mice hippocampus. Sodium valproate (VPA) was used as a standard anti-epileptic drug. Methods: Mice were assigned into five groups (n=15): control, SeNPs (5 mg/kg, orally), PTZ (60 mg/kg, intraperitoneally), SeNPs+PTZ and VPA (200 mg/kg)+PTZ. All groups were treated for 10 days. Results: PTZ injection triggered a state of oxidative stress in the hippocampal tissue as represented by the elevated lipoperoxidation, heat shock protein 70 level, and nitric oxide formation while decreased glutathione level and antioxidant enzymes activity. Additionally, the blotting analysis showed downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the epileptic mice. A state of neuroinflammation was recorded following the developed seizures represented by the increased pro-inflammatory cytokines. Moreover, neuronal apoptosis was recorded following the development of epileptic convulsions. At the neurochemical level, acetylcholinesterase activity and monoamines content were decreased in the epileptic mice, accompanied by high glutamate and low GABA levels in the hippocampal tissue. However, SeNP supplementation was found to delay the onset and decreased the duration of tonic, myoclonic, and generalized seizures following PTZ injection. Moreover, SeNPs were found to provide neuroprotection through preventing the development of oxidative challenge via the upregulation of Nrf2 and HO-1, inhibiting the inflammatory response and apoptotic cascade. Additionally, SeNPs reversed the changes in the activity and levels of neuromodulators following the development of epileptic seizures. Conclusion: The obtained results suggest that SeNPs could be used as a promising anticonvulsant drug due to its potent antioxidant, anti-inflammatory, and neuromodulatory activities.
The limbic system plays a pivotal role in stress-induced anxiety and intestinal disorders, but how the functional circuits between nuclei within the limbic system are engaged in the processing is still unclear. In our study, the results of fluorescence gold retrograde tracing and fluorescence immunohistochemistry showed that the melanin-concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) projected to the basolateral amygdala (BLA). Both chemogenetic activation of MCH neurons and microinjection of MCH into the BLA induced anxiety disorder in mice, which were reversed by intra-BLA microinjection of MCH receptor 1 (MCHR1) blocker SNAP-94847. In the chronic acute combining stress (CACS) stimulated mice, SNAP94847 administrated in the BLA ameliorated anxiety-like behaviors and improved intestinal dysfunction via reducing intestinal permeability and inflammation. In conclusion, MCHergic circuit from the LHA to the BLA participates in the regulation of anxiety-like behavior in mice, and this neural pathway is related to the intestinal dysfunction in CACS mice by regulating intestinal permeability and inflammation.
Irritable bowel syndrome (IBS) is characterized by gastrointestinal dysmotility and visceral hyperalgesia, and the impaired brain-gut axis is accepted as a crucial cause for the onset of IBS. The objective of this study is to investigate the effects of the adaptive changes in the central neural system induced by stress on IBSlike syndromes in rats. Long-term water avoidance stress (WAS) was used to prepare IBS animals. The changes in neuronal excitation and GABA expression were shown by immunohistochemistry. The mRNA and protein expressions of neurotransmitters were detected with Quantitative reverse-transcription PCR (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA). The intestinal transit time, fecal moisture content, and abdominal withdrawal reflex scores of rats were recorded to monitor intestinal motility and visceral hyperalgesia. In the WAS-treated rats with enhanced intestinal motility and visceral hypersensitivity, more GABAergic projections were found in the paraventricular nucleus (PVN) of the hypothalamus, which inhibited the firing rate of neurons and decreased the expression of oxytocin. Exogenous oxytocin improved gut motility and decreased AWR scores. The inhibition of oxytocin by the adaptive GABAergic projection in the PVN might be an important mediator of IBS, which indicates a potential novel therapeutic target.
Background: Impaired bidirectional communication between the gastrointestinal tract and the central nervous system (CNS) is closely related to the development of irritable bowel syndrome (IBS). Studies in patients with IBS have also shown significant activation of the hypothalamus and amygdala. However, how neural circuits of the CNS participate in and process the emotional and intestinal disorders of IBS remains unclear.
Methods:The GABAergic neural pathway projecting from the central amygdala (CeA) to the lateral hypothalamus (LHA) in mice was investigated by retrograde tracking combined with fluorescence immunohistochemistry. Anxiety, depression-like behavior, and intestinal motility were observed in the water-immersion restraint stress group and the control group. Furthermore, the effects of the chemogenetic activation of the GABAergic neural pathway of CeA-LHA on behavior and intestinal motility, as well as the co-expression of orexin-A and c-Fos in the LHA, were explored.
The aging process is characterized by a progressive decline of metabolic functions, insulin resistance, and cognitive impairment. We and others have reported that Growth Hormone Secretagogue Receptor (GHS‐R) plays a crucial role in metabolic regulation. GHS‐R is an endogenous G‐protein coupled receptor for the gut hormone ghrelin, and ghrelin signals the hypothalamus to increase feeding, decrease energy expenditure and reduce fat utilization. We previously reported that global GHS‐R deletion leads to a healthier metabolic profile compared to WT littermates in aging mice. We showed that ablation of GHS‐R ameliorates age‐associated metabolic impairments, reducing body weight/adiposity and improving insulin sensitivity during aging. Furthermore, we found that suppression of GHS‐R in neurons almost completely prevents diet‐induced obesity in mice (Syn1‐cre;Ghsrf/f), likely through increasing energy expenditure. Here, we further assessed metabolic and memory functions of 18–20 months‐old Syn1‐cre;Ghsrf/f and littermate Ghsrf/f control mice. Similar to young mice, old Syn1‐cre;Ghsrf/f mice showed reduced body weight and adiposity. Consistently, old Syn1‐cre;Ghsrf/f mice are more insulin sensitive than littermate controls. Interestingly, old Syn1‐cre;Ghsrf/f mice spent significantly more time exploring the novel object than the familiar object compared to controls in the novel object recognition test, at both 2 hours and 24 hours after training. These data suggest that old Syn1‐cre;Ghsrf/f mice retained short‐term and long‐term memory better than their littermate controls. In addition, old Syn1‐cre;Ghsrf/f mice exhibited significantly increased freezing behavior in both contextual and conditioned auditory stimulus tests in fear conditioning assay, indicating that old Syn1‐cre;Ghsrf/f mice retained better hippocampal‐dependent and amygdala‐dependent memory function compared to littermate controls. Overall, our data suggest that pan‐neuronal deletion of GHS‐R attenuates aging‐associated obesity, insulin resistance and memory impairment. The metabolic benefits derived from suppression of GHS‐R resemble the effects of calorie restriction, the most recognized strategy for increasing health span in multiple organisms. GHS‐R may provide a novel molecular target for improving metabolic fitness and cognitive function during aging.
Support or Funding Information
We gratefully acknowledges the support of NIH R56DK118334 (YS), NIA R01AG064869 (YS), and NIA R21AG061726 (CW).
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