The place of beta-adrenergic receptor blockers in the treatment of arterial hypertension: from bench-to-bedside.

Arterial hypertension is a multifaceted condition influenced by numerous pathophysiological factors. The key contributors to its pathogenesis encompass an unhealthy lifestyle, dysregulation of the sympathetic nervous system, alterations in the activity of adrenergic receptors, disruptions in sodium metabolism, structural and functional abnormalities in the vascular bed, as well as endothelial dysfunction, low-grade inflammation, oxidative stress etc. Despite extensive research into the mechanisms of arterial hypertension development over the centuries, its pathogenesis remains incompletely understood, and the selection of an effective treatment strategy continues to pose a significant challenge. Arterial hypertension is characterized by a diminished sensitivity of the ß-adrenergic system, leading to the utilization of ß-adrenergic blockers and other antihypertensive drugs in its treatment. This review delves into the mechanisms of action of beta-adrenergic receptor blockers in the treatment of hypertension and their respective effects.

Significant Interaction between Melatonin and Titanium Bone Implants: Available Evidence and Future Research Directions.

The trend in the incidence rate of bone fractures has been upward and as a result, the burden associated with orthopedic fractures has increased significantly. Titanium (Ti) implants are considered a preferred method of managing long bone fractures. However, no benefit comes without some downside, and using Ti implants is associated with several complications. In this respect, it was observed that in bones, Ti can disrupt the bone healing process by disturbing the balance of osteoclast and osteoblast activation and also increasing the production of inflammatory cytokines. Melatonin is a widely-acting molecule that possesses strong anti-oxidant features. This molecule reinforces mineral density and improves bone formation processes. In this review, we focused on the protective effect of melatonin in mitigating the Ti-related complications.

Anti-inflammatory and protective effects of Aripiprazole on TNBS-Induced colitis and associated depression in rats: Role of kynurenine pathway.

BACKGROUND: The prevalence of depression is higher in patients with inflammatory bowel disease (IBD) than in the general population. Inflammatory cytokines and the kynurenine pathway (KP) play important roles in IBD and associated depression. Aripiprazole (ARP), an atypical antipsychotic, shows various anti-inflammatory properties and may be useful in treating major depressive disorder. This study aimed to evaluate the protective effects of ARP on TNBS-induced colitis and subsequent depression in rats, highlighting the role of the KP. MATERIAL AND METHODS: Fifty-six male Wistar rats were used, and all groups except for the normal and sham groups received a single dose of intra-rectal TNBS. Three different doses of ARP and dexamethasone were injected intraperitoneally for two weeks in treatment groups. On the 15th day, behavioral tests were performed to evaluate depressive-like behaviors. Colon ulcer index and histological changes were assessed. The tissue levels of inflammatory cytokines, KP markers, lipopolysaccharide (LPS), nuclear factor-kappa-B (NF-κB), and zonula occludens (ZO-1) were evaluated in the colon and hippocampus. RESULTS: TNBS effectively induced intestinal damages and subsequent depressive-like symptoms in rats. TNBS treatment significantly elevated the intestinal content of inflammatory cytokines and NF-κB expression, dysregulated the KP markers balance in both colon and hippocampus tissues, and increased the serum levels of LPS. However, treatment with ARP for 14 days successfully reversed these alterations, particularly at higher doses. CONCLUSION: ARP could alleviate IBD-induced colon damage and associated depressive-like behaviors mainly via suppressing inflammatory cytokines activity, serum LPS concentration, and affecting the NF-κB/kynurenine pathway.

Melatonin and oral diseases: possible therapeutic roles based on cellular mechanisms.

Oral diseases, including periodontal disorders, oral cancer, periodontitis, and mucositis are the major challenges for both patients and healthcare providers. These conditions often involve inflammation, oxidative stress, and impaired cellular processes, leading to symptoms ranging from discomfort to severe debilitation. Conventional treatments for such oral diseases exhibit constraints, prompting the investigation of innovative therapeutic approaches. Considering the anti-inflammatory, anti-oxidant, and anti-cancer effects of melatonin, this study was carried out to investigate the potential protective effects of melatonin in mitigating the severity of oral diseases. Studies indicate that melatonin influences the differentiation of periodontal stem cells, inhibits oral cancer progression, reduces inflammation associated with periodontitis, and alleviates the severity of oral mucositis. Melatonin has demonstrated potential efficacy in both preclinical and clinical investigations; however, findings are frequently heterogeneous and contingent upon contextual factors. This review provides a comprehensiveoverview of current state of knowledge in this domain, elucidating the multifaceted role that melatonin may assume in combatingoral diseases. Further research should be directed toward determining the most effective dosing, timing, and administration methods for melatonin-based therapies for oral diseases.

Novel synthesized ionizable lipid for LNP-mediated P2X7siRNA to inhibit migration and induce apoptosis of breast cancer cells.

The development of ionizable lipid (IL) was necessary to enable the effective formulation of small interfering RNA (siRNA) to inhibit P2X7 receptors (P2X7R), a key player in tumor proliferation, apoptosis, and metastasis. In this way, the synthesis and utility of IL for enhancing cellular uptake of lipid nanoparticles (LNP) improve the proper delivery of siRNA-LNPs for knockdown overexpression of P2X7R. Therefore, to evaluate the impact of P2X7 knockdown on breast cancer (BC) migration and apoptosis, a branched and synthesized ionizable lipid (SIL) was performed for efficient transfection of LNP with siRNA for targeting P2X7 receptors (siP2X7) in mouse 4T-1 cells. Following synthesis and structural analysis of SIL, excellent characterization of the LNP was achieved (Z-average 126.8 nm, zeta-potential - 12.33, PDI 0.16, and encapsulation efficiency 85.35%). Afterward, the stability of the LNP was evaluated through an analysis of the leftover composition, and toxic concentration values for SIL and siP2X7 were determined. Furthermore, siP2X7-LNP cellular uptake in the formulation was assessed via confocal microscopy. Following determining the optimal dose (45 pmol), wound healing analysis was assessed using scratch assay microscopy, and apoptosis was evaluated using flow cytometry. The use of the innovative branched SIL in the formulation of siP2X7-LNP resulted in significant inhibition of migration and induction of apoptosis in 4T-1 cells due to improved cellular uptake. Subsequently, the innovative SIL represents a critical role in efficiently delivering siRNA against murine triple-negative breast cancer cells (TNBC) using LNP formulation, resulting in significant efficacy.

Sumatriptan mitigates bleomycin-induced lung fibrosis in male rats: Involvement of inflammation, oxidative stress and α-SMA.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung condition that produces symptoms including coughing which may cause by excessive accumulation of scar tissue inflammatory and oxidative stress exacerbation. Sumatriptan, utilized for migraine treatment as a selective 5-HT1B/1D receptor agonist, has demonstrated significant anti-inflammatory and antioxidant properties in multiple preclinical investigations. Operating primarily on serotonin receptors, sumatriptan leverages the diverse physiological functions of serotonin, playing a pivotal role in regulating both inflammation and oxidative stress which is particularly relevant in the context of IPF. MATERIALS & METHODS: Thirty-five male Wistar rats were divided to five group, including: Sham (without IPF induction), control (BLM 5 mg/kg, intraperitoneally), and three fibrosis group with sumatriptan (0.5, 1, and 3 mg/kg, i.p. for 2 weeks) administration. IPF was induced by injection of BLM (single dose, 5 mg/kg intratracheally). Lung tissues were separated for measurement of myeloperoxidase (MPO) as an oxidative stress hallmark, and tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-ß), and transforming growth factor-ß (TGF-ß) as inflammatory markers as well as alpha smooth muscle actin (α-SMA). Also, for histological investigations, tissue damages were assessed by Hematoxylin-eosin (H&E) and Masson's trichrome staining method. RESULTS: BLM-induced fibrosis could increase α-SMA, MPO, TNF-α, IL-1ß, and TGF-ß, while treatment with sumatriptan has reversed the α-SMA, MPO, and IL-1ß levels. Moreover, the results of H&E and Masson's trichrome staining indicated that sumatriptan (1 and 3 mg/kg) reduced tissue damages, alveolar wall thickness, collagen accumulation, and pulmonary fibrosis induced by BLM. CONCLUSION: According to the data achieved from this study, Sumatriptan appears to have therapeutic benefits in IPF, possibly via reducing α-SMA as well as inflammation and the toxicity caused by oxidative stress.

Melatonin: Current evidence on protective and therapeutic roles in gynecological diseases.

Melatonin, a potent antioxidant and free radical scavenger, has been demonstrated to be effective in gynecological conditions and female reproductive cancers. This review consolidates the accumulating evidence on melatonin's multifaceted protective effects in different pathological contexts. In gynecological conditions such as endometriosis, polycystic ovary syndrome (PCOS), and uterine leiomyoma, melatonin has shown promising effects in reducing oxidative stress, inflammation, and hormonal imbalances. It inhibits adhesion molecules' production, and potentially mitigates leukocyte adherence and inflammatory responses. Melatonin's regulatory effects on hormone production and insulin sensitivity in PCOS individuals make it a promising candidate for improving oocyte quality and menstrual irregularities. Moreover, melatonin exhibits significant antitumor effects by modulating various signaling pathways, promoting apoptosis, and suppressing metastasis in breast cancers and gynecological cancers, including ovarian, endometrial, and cervical cancers. Furthermore, melatonin's protective effects are suggested to be mediated by interactions with its receptors, estrogen receptors and other nuclear receptors. The regulation of clock-related genes and circadian clock systems may also contribute to its inhibitory effects on cancer cell growth. However, more comprehensive research is warranted to fully elucidate the underlying molecular mechanisms and establish melatonin as a potential therapeutic agent for these conditions.

Comparison of neuroprotective effects of a topiramate-loaded biocomposite based on mesoporous silica nanoparticles with pure topiramate against methylphenidate-induced neurodegeneration.

BACKGROUND: Methylphenidate (MPH) abuse has been criticized for its role in neurodegeneration. Also, a high risk of seizure was reported in the first month of MPH treatment. Topiramate, a broad-spectrum Antiepileptic Drug (AED), has been used as a neuroprotective agent in both aforementioned complications. Nanotechnology is introduced to increase desirable neurological treatment with minimum side effects. We aimed to investigate the potential neuroprotective activity of topiramate loaded on nanoparticles. METHODS AND RESULTS: MTT assay was performed to evaluate the cellular cytotoxicity of Mesoporous Silica Nanoparticles (MSN). Male rats were randomly divided into eight groups. Rats received an intraperitoneal (i.p) MPH (10 mg/kg) injection and a daily oral dose of topiramate (TPM, 30 mg/kg), MSN with Zn core (10 and 30 mg/kg), and MSN with Cu core (10 and 30 mg/kg) for three weeks. On day 21, a seizure was induced by a single injection of pentylenetetrazole (PTZ) to evaluate the protective effects of TPM-loaded nanoparticles on seizure latency and duration following MPH-induced neurotoxicity. Moreover, the hippocampal content of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), malondialdehyde (MDA), and the anti-oxidant enzymes (SOD, GPx, and GR) activities were assessed. Also, BAX and Bcl-2 as two main apoptotic markers were evaluated. RESULTS: MPH neurotoxicity was observed as a raised duration and reduced latency in PTZ-induced seizure. However, TPM-loaded MSN with Zn species (NE) treatment reduced the duration and improved the latency time. Also, NE and, somewhat, TPM-loaded MSN with Cu species (NM) administration reduced inflammatory cytokines, MDA, and Bax levels and increased activities in the rat hippocampus. CONCLUSION: TPM-loaded nanoparticles could be used as neuroprotective agents against MPH-induced neurodegeneration by improving seizure parameters and reducing inflammatory, oxidant, and apoptotic factors.

Ivermectin ameliorates bleomycin-induced lung fibrosis in male rats by inhibiting the inflammation and oxidative stress.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a pulmonary fibrotic disease characterized by a poor prognosis, which its pathogenesis involves the accumulation of abnormal fibrous tissue, inflammation, and oxidative stress. Ivermectin, a positive allosteric modulator of GABAA receptor, exerts anti-inflammatory and antioxidant properties in preclinical studies. The present study investigates the potential protective effects of ivermectin treatment in rats against bleomycin-induced IPF. MATERIALS AND METHODS: The present study involved 42 male Wistar rats, which were divided into five groups: control (without induction of IPF), bleomycin (IPF-induced by bleomycin 2.5 mg/kg, by intratracheal administration), and three fibrosis groups receiving ivermectin (0.5, 1, and 3 mg/kg). lung tissues were harvested for measurement of oxidative stress [via myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH)] and inflammatory markers (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß], and transforming growth factor-ß [TGF-ß]). Histological assessments of tissue damage were performed using hematoxylin-eosin (H&E) and Masson's trichrome staining methods. RESULTS: The induction of fibrosis via bleomycin was found to increase levels of MPO as well as TNF-α, IL-1ß, and TGF-ß while decrease SOD activity and GSH level. Treatment with ivermectin at a dosage of 3 mg/kg was able to reverse the effects of bleomycin-induced fibrosis on these markers. In addition, results from H&E and Masson's trichrome staining showed that ivermectin treatment at this same dose reduced tissue damage and pulmonary fibrosis. CONCLUSION: The data obtained from this study indicate that ivermectin may have therapeutic benefits for IPF, likely due to its ability to reduce inflammation and mitigate oxidative stress-induced toxicity.

Cross state-dependent memory retrieval between tramadol and ethanol: involvement of dorsal hippocampal GABAA receptors.

RATIONALE: Tramadol and ethanol, as psychoactive agents, are often abused. Discovering the molecular pathways of drug-induced memory creation may contribute to preventing drug addiction and relapse. OBJECTIVE: The tramadol- and ethanol-induced state-dependent memory (SDM) and cross-SDM retrieval between tramadol and ethanol were examined in this study. Moreover, because of the confirmed involvement of GABAA receptors and GABAergic neurotransmission in memory retrieval impairment, we assessed cross-SDM retrieval between tramadol and ethanol with a specific emphasis on the role of the GABAA receptors. The first hypothesis of this study was the presence of cross-SDM between tramadol and ethanol, and the second hypothesis was related to possible role of GABAA receptors in memory retrieval impairment within the dorsal hippocampus. The cannulae were inserted into the hippocampal CA1 area of NMRI mice, and a step-down inhibitory avoidance test was used to evaluate state dependence and memory recovery. RESULTS: The post-training and/or pre-test administration of tramadol (2.5 and 5 mg/kg, i.p.) and/or ethanol (0.5 and 1 g/kg, i.p.) induced amnesia, which was restored after the administration of the drugs 24 h later during the pre-test period, proposing ethanol and tramadol SDM. The pre-test injection of ethanol (0.25 and 0.5 g/kg, i.p.) with tramadol at an ineffective dose (1.25 mg/kg) enhanced tramadol SDM. Moreover, tramadol injection (1.25 and 2.5 mg/kg) with ethanol at the ineffective dose (0.25 g/kg) promoted ethanol SDM. Furthermore, the pre-test intra-CA1 injection of bicuculline (0.0625, 0.125, and 0.25 µg/mouse), a GABAA receptor antagonist, 5 min before the injection of tramadol (5 mg/kg) or ethanol (1 g/kg) inhibited tramadol- and ethanol-induced SDM dose-dependently. CONCLUSION: The findings strongly confirmed cross-SDM between tramadol and ethanol and the critical role of dorsal hippocampal GABAA receptors in the cross-SDM between tramadol and ethanol.

Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis.

Fibrosis, the excessive deposition of fibrous connective tissue in an organ in response to injury, is a pathological condition affecting many individuals worldwide. Fibrosis causes the failure of tissue function and is largely irreversible as the disease progresses. Pharmacologic treatment options for organ fibrosis are limited, but studies suggest that antioxidants, particularly melatonin, can aid in preventing and controlling fibrotic damage to the organs. Melatonin, an indole nocturnally released from the pineal gland, is commonly used to regulate circadian and seasonal biological rhythms and is indicated for treating sleep disorders. While it is often effective in treating sleep disorders, melatonin's anti-inflammatory and antioxidant properties also make it a promising molecule for treating other disorders such as organ fibrosis. Melatonin ameliorates the necrotic and apoptotic changes that lead to fibrosis in various organs including the heart, liver, lung, and kidney. Moreover, melatonin reduces the infiltration of inflammatory cells during fibrosis development. This article outlines the protective effects of melatonin against fibrosis, including its safety and potential therapeutic effects. The goal of this article is to provide a summary of data accumulated to date and to encourage further experimentation with melatonin and increase its use as an anti-fibrotic agent in clinical settings.

Protective and therapeutic potential of melatonin against intestinal diseases: updated review of current data based on molecular mechanisms.

INTRODUCTION: Intestinal diseases, a leading global cause of mortality and morbidity, carry a substantial socioeconomic burden. Small and large intestines play pivotal roles in gastrointestinal physiology and food digestion. Pathological conditions, such as gut dysbiosis, inflammation, cancer, therapy-related complications, ulcers, and ischemia, necessitate the urgent exploration of safe and effective complementary therapeutic strategies for optimal intestinal health. AREAS COVERED: This article evaluates the potential therapeutic effects of melatonin, a molecule with a wide range of physiological actions, on intestinal diseases including inflammatory bowel disease, irritable bowel syndrome, colon cancer, gastric/duodenal ulcers and other intestinal disorders. EXPERT OPINION: Due to anti-inflammatory and antioxidant properties as well as various biological actions, melatonin could be a therapeutic option for improving digestive disorders. However, more researches are needed to fully understand the potential benefits and risks of using melatonin for digestive disorders.

Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases.

Tryptophan metabolism along the kynurenine pathway is of central importance for the immune function. It prevents hyperinflammation and induces long-term immune tolerance. Accumulating evidence also demonstrates cytoprotective and immunomodulatory properties of kynurenine pathway in conditions affecting either central or peripheral nervous system as well as other conditions such as inflammatory bowel disease (IBD). Although multilevel association exists between the inflammatory bowel disease (IBD) and various neurologic (e.g., neurodegenerative) disorders, it is believed that the kynurenine pathway plays a pivotal role in the development of both IBD and neurodegenerative disorders. In this setting, there is strong evidence linking the gut-brain axis with intestinal dysfunctions including IBD which is consistent with the fact that the risk of neurodegenerative diseases is higher in IBD patients. This review aims to highlight the role of kynurenine metabolic pathway in various neurologic and psychiatric diseases as well as relationship between IBD and neurodegenerative disorders in the light of the kynurenine metabolic pathway.

Possibilities of dapagliflozin-induced cardioprotection on doxorubicin + cyclophosphamide mode of chemotherapy-induced cardiomyopathy.

RATIONALE: The global burden of cardiovascular (CV) and oncological diseases continues to increase. In this regard, the prevention of CV diseases (CVD) before and after cancer treatment is an urgent and unsolved problem in medicine. For this reason, our research group aimed to investigate the possibility of dapagliflozin-related cardioprotection, using an experimental model of chronic Doxorubicin (Adriamycin) + Cyclophosphamide (AC)-mode of chemotherapy-induced cardiomyopathy. OBJECTIVE: The redox balance, lipid metabolism, endothelial dysfunction, and myocardial damage parameters were measured to evaluate the pathways of dapagliflozin-induced stabilization of CV homeostasis. METHODS: For this study, 80 inbred Wistar rats were randomly assigned to four equally sized groups. A model of chronic cardiotoxicity was attained by using doxorubicin and cyclophosphamide co-administration. In the case, the markers of redox-balance, cholesterol metabolism, endothelial dysfunction, myocardial alteration, and morphological examination were assessed. RESULTS: For all parameters, statistically significant deviations were obtained, emphasizing the sequel of AC-mode chemotherapy-related detergent effect on CV system (group 2). Moreover, the data obtained from dapagliflozin-treated groups (group 3) showed that this strategy provide limitation of lipid peroxidation, cholesterol metabolism and endothelial function normalization, with subsequent morphological preservation of myocardium. CONCLUSION: Dapagliflozin has a broad spectrum of pleiotropic influences, namely cholesterol-lowering, anti-inflammatory, and endothelium-stabilizing properties. These properties provide a favorable environment for the prevention of chemotherapy-related cardiomyopathy.

Nano-immunotherapy: overcoming delivery challenge of immune checkpoint therapy.

Immune checkpoint (ICP) molecules expressed on tumor cells can suppress immune responses against tumors. ICP therapy promotes anti-tumor immune responses by targeting inhibitory and stimulatory pathways of immune cells like T cells and dendritic cells (DC). The investigation into the combination therapies through novel immune checkpoint inhibitors (ICIs) has been limited due to immune-related adverse events (irAEs), low response rate, and lack of optimal strategy for combinatorial cancer immunotherapy (IMT). Nanoparticles (NPs) have emerged as powerful tools to promote multidisciplinary cooperation. The feasibility and efficacy of targeted delivery of ICIs using NPs overcome the primary barrier, improve therapeutic efficacy, and provide a rationale for more clinical investigations. Likewise, NPs can conjugate or encapsulate ICIs, including antibodies, RNAs, and small molecule inhibitors. Therefore, combining the drug delivery system (DDS) with ICP therapy could provide a profitable immunotherapeutic strategy for cancer treatment. This article reviews the significant NPs with controlled DDS using current data from clinical and pre-clinical trials on mono- and combination IMT to overcome ICP therapeutic limitations.

Melatonin and bone-related diseases: an updated mechanistic overview of current evidence and future prospects.

PURPOSE: Bone diseases account for an enormous cost burden on health systems. Bone disorders are considered as age-dependent diseases. The aging of world population has encouraged scientists to further explore the most effective preventive modalities and therapeutic strategies to overcome and reduce the high cost of bone disorders. Herein, we review the current evidence of melatonin's therapeutic effects on bone-related diseases. METHODS: This review summarized evidences from in vitro, in vivo, and clinical studies regarding the effects of melatonin on bone-related diseases, with a focus on the molecular mechanisms. Electronically, Scopus and MEDLINE®/PubMed databases were searched for articles published on melatonin and bone-related diseases from inception to June 2023. RESULTS: The findings demonstrated that melatonin has beneficial effect in bone- and cartilage-related disorders such as osteoporosis, bone fracture healing, osteoarthritis, and rheumatoid arthritis, in addition to the control of sleep and circadian rhythms. CONCLUSION: A number of animal and clinical studies have indicated that various biological effects of melatonin may suggest this molecule as an effective therapeutic agent for controlling, diminishing, or suppressing bone-related disorders. Therefore, further clinical studies are required to clarify whether melatonin can be effective in patients with bone-related diseases.

HIV-Related Atherosclerosis: State-of-the-Art-Review.

The infection caused by the Human Immunodeficiency Virus (HIV) has spread rapidly across the globe, assuming the characteristics of an epidemic in some regions. Thanks to the introduction of antiretroviral therapy into routine clinical practice, there was a considerable breakthrough in the treatment of HIV, that is now HIV is potentially well-controlled even in low-income countries. To date, HIV infection has moved from the group of life-threatening conditions to the group of chronic and well controlled ones and the quality of life and life expectancy of HIV+ people, with an undetectable viral load is closer to that of an HIV- people. However, unsolved issues still persist. For example: people living with HIV are more prone to the age-related diseases, especially atherosclerosis. For this reason, a better understanding of the mechanisms of HIV-associated destabilization of vascular homeostasis seems to be an urgent duty, that may lead to the development of new protocols, bringing the possibilities of pathogenetic therapies to a new level. The purpose of the article was to evaluate the pathological aspects of HIV-induced atherosclerosis.

Orexin receptor antagonists in the pathophysiology and treatment of sleep disorders and epilepsy.

The correlation between sleep and epilepsy has been argued over the past decades among scientists. Although the similarities and contrasts between sleep and epilepsy had been considered, their intertwined nature was not revealed until the nineteenth century. Sleep is recognized as a recurring state of mind and body through alternating brain electrical activities. It is documented that sleep disorders are associated with epilepsy. The origin, suppression, and spread of seizures are affected by sleep. As such, in patients with epilepsy, sleep disorders are a frequent comorbidity. Meanwhile, orexin, a wake-promoting neuropeptide, provides a bidirectional effect on both sleep and epilepsy. Orexin and its cognate receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R), orchestrate their effects by activating various downstream signaling pathways. Although orexin was considered a therapeutic target in insomnia shortly after its discovery, its potential usefulness for psychiatric disorders and epileptic seizures has been suggested in the pre-clinical studies. This review aimed to discuss whether the relationship between sleep, epilepsy, and orexin is clearly reciprocal.

Spermidine reduced neuropathic pain in chronic constriction injury-induced peripheral neuropathy in rats.

Neuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into three groups: sham, CCI and CCI+SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3 weeks. The behavioral tests (von Frey, hot plate) were done four times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significantly lower in the CCI group than in the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P < 0.01, P < 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of superoxide dismutase (SOD), glutathione (GPx), and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress and improved histopathological changes and behavioral tests in the CCI-induced neuropathic pain in in vivo model.