The hippocampal-prefrontal cortex network dynamics is reported to be involved in various cognitive functions and in different mood disturbances including depression. It has been suggested that blocking orexin-1 receptors can be beneficial in depression. The purpose of this study is to determine whether orexin-1 receptor antagonists have an impact on changes in brain oscillations in the hippocampus and prefrontal cortex in a rat model of depression. Forty-eight male Wistar rats were divided into six experimental groups: control, chronic mild stress (CMS), acute SB-334867, a selective orexin-1 receptor antagonist, treated rats (SB), chronic SB-treated (CSB), CMS+SB, and CMS+CSB. Two stainless steel recording electrodes were placed in the coordinates of the hippocampus (HPC) and the prefrontal cortex (PFC). After behavioral verification of the model, local field potentials were recorded at 1 kHz sampling frequency. The absolute power of different frequency bands was obtained using the Fast Fourier Transform (FFT) function, and the power spectral density (PSD) of each frequency band was calculated for each animal. In the CMS- treated animals, the low-gamma band power increased both in the HPC and PFC (p ≤ 0.05), which were reversed by chronic SB-334867 treatment (p ≤ 0.05). The alterations in theta, and high-gamma band power were not significant in CMS treated rats, while acute and chronic SB-334867 treatment diminished the theta and high-gamma band power (p ≤ 0.05), respectively. The hippocampal-prefrontal coherence decreased in the delta (p ≤ 0.01), theta (p ≤ 0.01), and alpha (p ≤ 0.05) band range of the CMS exposed rats. It is concluded that CMS boosts the low-gamma band power, which is reversed by CSB treatment. The low-frequency band coherence is attenuated after CMS treatment.

2023-01-01·CNS drugs

Orexin Receptor Antagonists in the Treatment of Depression: A Leading Article Summarising Pre-clinical and Clinical Studies

Article

作者: Jones, Edward ; Fagan, Harry ; Baldwin, David S

The orexin (hypocretin) system comprises two neuropeptides (orexin-A and orexin-B) and two G-protein coupled receptors (the orexin type 1 and the orexin type 2 receptor). The system regulates several biological functions including appetite, the sleep-wake cycle, the stress response, and motivation and reward processing. Dysfunction of the orexin system has been implicated in the pathophysiology of depression in human and animal studies, although the exact nature of this dysfunction remains unclear. Orexin receptor antagonists (ORAs) are a class of compounds developed for the treatment of insomnia and have demonstrated efficacy in this area. Three dual orexin receptor antagonists (DORAs) have received licences for treatment of primary insomnia and some ORAs have since been investigated as potential treatments for major depressive disorder (MDD). In this leading article, we summarise the existing literature on use of ORAs in depression, in pre-clinical and clinical studies. In rodent models of depression, investigated ORAs have included the DORA almorexant and TCS1102, the selective orexin 1 receptor antagonists SB334867 and SB674042 and the selective orexin 2 receptor antagonists LSN2424100, MK-1064 and TCS-OX2-29. These pre-clinical studies suggest a possible antidepressant effect of systemic DORA treatment, however the evidence from selective ORAs is conflicting. To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo.

2022-01-01·Therapeutic Advances in Endocrinology and Metabolism4区 · 医学

Pharmacotherapy to delay the progression of diabetic kidney disease in people with type 2 diabetes: past, present and future

4区 · 医学

ReviewOA

作者: Chowdhury, Tahseen A. ; Mallik, Ritwika

Diabetic kidney disease (DKD) is a leading cause of morbidity and mortality among people living with diabetes, and is one of the most important causes of end stage renal disease worldwide. In order to reduce progression of DKD, important management goals include treatment of hypertension, glycaemia and control of cardiovascular risk factors such as lipids, diet, smoking and exercise. Use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers has an established role in prevention of progression of DKD. A number of other agents such as endothelin-1 receptor antagonists and bardoxolone have had disappointing results. Recent studies have, however, suggested that newer antidiabetic agents such as sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 analogues have specific beneficial effects in patients with DKD. Indeed most recent guidance suggest that SGLT-2i drugs should be used early in DKD, irrespective of glucose control. A number of pathways are hypothesised for the development and progression of DKD, and have opened up a number of newer potential therapeutic targets. This article aims to discuss management of DKD with respect to seminal trials from the past, more recent trials informing the present and potential new therapeutic options that may be available in the future.

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