Simvastatin improves learning and memory impairment via gut-brain axis regulation in an ovariectomized/D-galactose Alzheimer's rat model.

AIM: Alzheimer's disease (AD) is the most prevalent form of dementia with multiple etiology and no effective remedy. Statins are a group of medicines that are basically used to lower cholesterol. However, several studies have recently done to assess the potential relationship between statins use and dementia but presented controversial results. METHODS: In this study, using ovariectomy and D-galactose injection, a model of AD was induced in female rats, and then the protective effects of oral administration of simvastatin were investigated. shuttle box and Y-maze tests were done to assess the animals' learning and memory performance. Using GC-MC, ELISA, Immunohistochemistry and tissue staining techniques, changes in the amount of short-chain fatty acids (SCFAs), plasma and hippocampus neuroinflammatory markers and histological changes in the intestine and hippocampus were assessed in sham, disease and treatment groups. KEY FINDINGS: Oral administration of simvastatin improved the gut microbiome activity (increased the amount of SCFAs in fecal samples) and strengthened the tight junctions of intestinal cells. Moreover, simvastatin reduced the amount of TNF-α and IL-1ß in plasma and hippocampus. Also, cell death and Amyloid plaques notably decreased in the simvastatin-treated hippocampal tissue. All these physiological changes led to better performance in behavioral tasks in the treatment group in comparison to the disease group. SIGNIFICANCE: These findings provide evidence that simvastatin may improve gut-brain axis followed by improvement in learning and memory via an anti-inflammatory effect.

Cross-talk between the HPA axis and addiction-related regions in stressful situations.

Addiction is a worldwide problem that has a negative impact on society by imposing significant costs on health care, public security, and the deactivation of the community economic cycle. Stress is an important risk factor in the development of addiction and relapse vulnerability. Here we review studies that have demonstrated the diverse roles of stress in addiction. Term searches were conducted manually in important reference journals as well as in the Google Scholar and PubMed databases, between 2010 and 2022. In each section of this narrative review, an effort has been made to use pertinent sources. First, we will provide an overview of changes in the Hypothalamus-Pituitary-Adrenal (HPA) axis component following stress, which impact reward-related regions including the ventral tegmental area (VTA) and nucleus accumbens (NAc). Then we will focus on internal factors altered by stress and their effects on drug addiction vulnerability. We conclude that alterations in neuro-inflammatory, neurotrophic, and neurotransmitter factors following stress pathways can impact related mechanisms on craving and relapse susceptibility.

Restoring the firing activity of ventral tegmental area neurons by lateral hypothalamic deep brain stimulation following morphine administration in rats.

We have previously shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) compromises morphine-induced addiction-like behavior in rats. The exact mechanism underlying this effect is not known. Here, we investigated the assumption that DBS in the LH influences the firing activity of neurons in the ventral tegmental area (VTA). To that end, male Wistar rats received morphine (5 mg/kg; s.c.) for three days and underwent extracellular single unit recording under general anesthesia one day later. During the recording, the rats received an intraoperative injection of morphine (5 mg/kg; s.c.) plus DBS in the LH (130 Hz pulse frequency, 150 µA amplitude, and 100 µs pulse width). One group of animals also received preoperative DBS after each morphine injection before the recording. The spiking frequency of VTA neurons was measured at three successive phases: (1) baseline (5-15 min); (2) DBS-on (morphine + DBS for 30 min); and (3) After-DBS (over 30 min after termination of DBS). Results showed that morphine suppressed the firing activity of a large population of non-DA neurons, whereas it activated most DA neurons. Intraoperative DBS reversed morphine suppression of non-DA firing, but did not alter the excitatory effect of morphine on DA neurons firing. With repeated preoperative application of DBS, non-DA neurons returned to the morphine-induced suppressive state, but DA neurons released from the excitatory effect of morphine. It is concluded that the development of morphine reward is associated with a hypoactivity of VTA non-DA neurons and a hyperactivity of DA neurons, and that DBS modulation of the spiking activity may contribute to the blockade of morphine addiction-like behavior.

The Therapeutic Activities of Metformin: Focus on the Nrf2 Signaling Pathway and Oxidative Stress Amelioration.

In the present study, the health-protective and therapeutic properties of MET have been discussed, focusing on the effect of MET on the Nrf2 expression in patients with different pathological conditions. Metformin (MET) regulates high blood glucose, thus being an integral part of the antidiabetic medications used to treat type 2 diabetes mellitus. It belongs to biguanide class medications that are administered through the oral route. Moreover, the agent is widely known for its anti-cancer, anti-oxidant, anti-inflammatory, and neuroprotective effects. The MET modulates the nuclear factor erythroid-2 related factor-2 (Nrf2) signaling pathway, which in turn yields the above-mentioned medical benefits to patients. The Nrf2 signaling pathways are modulated in multiple ways described subsequently: 1) MET acts on the cancer cells and inactivates Raf-ERK signaling, thus reducing Nrf2 expression, 2) MET obstructs the expression of proteins that are involved in apoptosis of tumor cells and also prevents tumor cells from oxidation through an AMPK-independent pathway; 3) MET carries out Keap1-independent mechanism for reducing the levels of Nrf2 protein in cancer cells; 4) MET upregulates the Nrf2-mediated transcription to stimulate the anti-oxidant process that prevents oxidative stress in cells system and consequently gives neuroprotection from rotenone and 5) MET downregulates p65 and upregulates Nrf2 which helps improve the angiogenesis impairment stimulated by gestational diabetes mellitus. This article presents an analysis of the health-protective properties of MET and also sheds light on the effect of MET on the Nrf2 expression in patients with different pathological conditions.

Deep brain stimulation of the lateral hypothalamus to block morphine reward: Does the intensity of stimulation matter?

It has been shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) prevents morphine-induced conditioned place preference (CPP) in rats. However, our previous study demonstrated that the application of DBS at 150 µA did not block morphine CPP in all rats. Here, we investigated the possibility to completely block morphine CPP by increasing the intensity of LH DBS. Morphine reward was assessed by the CPP paradigm in male Wistar rats. DBS was applied in the LH during the conditioning trials with morphine (5 mg/kg, S.C.) at 130 Hz pulse frequency, 100 µs pulse duration, and either 150 µA or 200 µA pulse amplitude. Results showed that repeated morphine injections produced a robust CPP that was blocked partially by DBS at 150 µA and completely by DBS at 200 µA. Response rate was 47% with 150-µA and 100% with 200-µA stimulation. DBS treatment was not associated with changes in motor activity. In conclusion, the development of morphine reward was modulated by LH DBS in an intensity-dependent manner.

Effects of Modafinil (Provigil) on Memory and Learning in Experimental and Clinical Studies: From Molecular Mechanisms to Behaviour Molecular Mechanisms and Behavioural Effects.

Modafinil (MOD, 2-diphenyl-methyl-sulphinil-2-acetamide) is a stimulant-like medicine used to treat narcolepsy. Off-label uses include improving cognitive ability in the course of other diseases. This review aims to discuss findings demonstrating the memory and learningenhancing activity of MOD in experimental and clinical studies. We included behavioral evaluations alongside the effects of MOD at the cellular and molecular level. MOD in different animal disease models exerted beneficial effects on induced memory and learning impairment, which in some cases were accompanied by modulation of neurotransmitter pathways or neuroplastic capabilities, reducing oxidative stress, or expression of synaptic proteins. Individuals treated with MOD showed improved memory and learning skills in different conditions. These effects were associated with regulating brain activity in some participants, confirmed by functional magnetic resonance imaging. Presented herein, data support the use of MOD in treating memory and learning deficits in various disease conditions.

Calcium dobesilate protects against d-galactose-induced hepatic and renal dysfunction, oxidative stress, and pathological damage.

Calcium dobesilate (CaD) is used for the treatment of diabetic retinopathy and nephropathy. This agent exerts antioxidant effects. In the present study, we evaluated the protective effects of oral administration of CaD against hepatorenal damages in a mice model of aging induced by d-galactose (d-gal). We used 28 male albino mice, which equally and randomly were divided into four groups as follows: intact, aging (d-gal at the dose of 500 mg/kg, p.o.), aging + CaD 50 (d-gal plus CaD at the dose of 50 mg/kg), and aging + CaD 100 (d-gal plus CaD at the dose of 100 mg/kg, p.o.). All drugs were administered orally once a day for 42 days. The liver and kidney damages were evaluated by measuring mass indices, levels of serum creatinine and blood urea nitrogen, and activities of serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and by histopathological evaluation. Moreover, hepatic and renal tissue oxidant/antioxidant markers (malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase) were measured. The results showed that d-gal treatment induced significant oxidative stress in the kidney and liver that was paralleled by dysfunctions and histological alterations of these organs. CaD significantly improved the liver and kidney indices, implemented functional capacity of the liver and kidney, as well as decreased oxidative stress enhancing antioxidative enzyme activities. CaD treatment also inhibited the development of histological alterations of both kidney and liver. CaD might represent a promising therapeutic agent for the attenuation of hepatorenal injuries induced by aging.

The interaction between sexual reward/ deprivation and the acquisition, extinction and reinstatement of morphine-seeking behavior.

Natural rewards and abused drugs affect the function of the common brain's reward system. Interaction between social and drug rewards can change the vulnerability to development of drug addiction. Here, we investigate the effects of sexual experience and sex deprivation on the acquisition, maintenance, and drug prime-induced reinstatement of morphine-seeking behavior in male mice using conditioned place preference (CPP). CPP induced with morphine (3, 5, 7 mg/kg, s.c. for 3 days) lasted for 10 days after cessation of morphine treatment and priming dose of morphine (2 mg/kg, s.c.) reinstated the extinguished CPP. In the post-test phase, sexually experienced animals showed a lower preference for morphine compared to sex-deprived males. In the extinction phase, sex deprivation shortened maintenance time compared to control animals. The preference for morphine in sexually experienced animals did not diminish by the seventeenth extinction day. In both groups, the priming injection of morphine after the extinction period could reinstate the extinguished morphine-induced CPP. Together, these data showed the interaction between sex and drug reward and that sexual behavior -a natural rewarding stimulus- can prolong, whereas sex deprivation can block the maintenance of morphine-seeking behaviors. Sexual experience may induce functional and morphological alterations in brain reward areas particularly the mesolimbic system similar to repeated exposure to abused drugs which can affect morphine-seeking behaviors.

Anti-LINGO-1 improved remyelination and neurobehavioral deficit in cuprizone-induced demyelination.

OBJECTIVES: Central nervous system demyelination is the main feature of multiple sclerosis (MS). The most important unmet need in MS is use of treatments that delay the progression of the disease. Leucine-rich repeat and Immunoglobulin-like domain containing NOGO receptor-interacting protein 1(LINGO-1) have been known as inhibitors of oligodendrocyte differentiation and myelination. MATERIALS AND METHODS: We investigated LINGO-1 antibody effects on remyelination and neurobehavioral deficit using cuprizone-induced demyelination. Animals were randomly divided into three groups (n = 10): (1) Control group; received the regular diet, (2) CPZ group; normal saline was injected intraperitoneally, and (3) Treatment group; LINGO-1 antibody (10 mg/kg) was injected IP once every six days for 3 weeks. We assessed the level of myelin basic protein (MBP), neurofilament heavy chain (NF200), and Brain-derived neuroprotective factor (BDNF) in the corpus callosum (CC) by immunostaining against MBP, NF200, and BDNF. RESULTS: We found decreased levels of MBP, NF200, and BDNF in demyelinated CC, and anti-LINGO-1 treatment improved demyelinated structures. Furthermore, motor impairment was measured by Open-field (OFT) and Balance beam tests. In the treatment group, motor impairment was significantly improved. CONCLUSION: These results provide evidence that LINGO-1 antibody can improve remyelination and neurobehavioral deficit.

Highlighting the Protective or Degenerative Role of AMPK Activators in Dementia Experimental Models.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR) Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide- 1-ß-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.

Carvacrol as a Potential Neuroprotective Agent for Neurological Diseases: A Systematic Review Article.

BACKGROUND AND OBJECTIVE: Neurological diseases are becoming a significant problem worldwide, with the elderly at a higher risk of being affected. Several researchers have investigated the neuroprotective effects of Carvacrol (CAR) (5-isopropyl-2-methyl phenol). This review systematically surveys the existing literature on the impact of CAR when used as a neuroprotective agent in neurological diseases. METHODS: The systematic review involved English articles published in the last ten years obtained from PubMed, Google Scholar, and Scopus databases. The following descriptors were used to search the literature: "Carvacrol" [Title] AND "neuroprotective (neuroprotection)" [Title] OR "stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, seizure, epilepsy [Title]. RESULTS: A total of 208 articles were retrieved during the search process, but only 20 studies met the eligibility criteria and were included for review. A total of 20 articles were identified, in which the efficacy of CAR was described in experimental models of stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, epilepsy, and seizure, through motor deficits improvements in neurochemical activity, especially antioxidant systems, reducing inflammation, oxidative stress and apoptosis as well as inhibition of TRPC1 and TRPM7. CONCLUSION: The data presented in this study support the beneficial impact of CAR on behavioural and neurochemical deficits. CAR benefits accrue because of its anti-apoptotic, antioxidant, and anti- inflammatory properties. Therefore, CAR has emerged as an alternative treatment for neurological disorders based on its properties.

Calcium Dobesilate Reverses Cognitive Deficits and Anxiety-Like Behaviors in the D-Galactose-Induced Aging Mouse Model through Modulation of Oxidative Stress.

The long-term treatment of mice with D-galactose (D-gal) induces the overproduction of reactive oxygen species (ROS) and is a well-accepted experimental model of oxidative stress-linked cognitive disorders in physiological aging. Calcium dobesilate (CaD, Doxium®) is an established vasoactive and angioprotective drug commonly used for the clinical treatment of diabetic retinopathy and chronic venous insufficiency. It has antioxidant properties and controls vascular permeability. In the current study, we evaluated the protective effects of CaD (50 and 100 mg/kg/day p.o.) in male mice treated with D-gal (500 mg/kg/day p.o.) for six weeks. Results demonstrated that body weight loss, anxiety-like and cognitive impairments of D-gal-treated animals were reversed by CaD administration as evaluated by the measurement of mice performance in elevated plus-maze, Y-maze, and shuttle box tests. CaD treatment also inhibited the oxidative stress in aging mouse brains by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities. These results could open new perspectives for the clinical use of CaD in treating and preventing cognitive impairment in older people.

Netrin-1 protects the SH-SY5Y cells against amyloid beta neurotoxicity through NF-κB/Nrf2 dependent mechanism.

Many evidence confirms that amyloid beta 1-42 fragment (Aß1-42) causes neuroinflammation, oxidative stress, and cell death, which are related to progressive memory loss, cognitive impairments and mental disorders that will lead to Alzheimer's disease (AD) progression. Netrin-1, as a member of the laminins, has been proved to inhibit apoptosis and inflammation outside of nervous system, in addition to having a vital role in morphogenesis and neurogenesis of neural system. This study was designed to assess the protective effects of netrin-1 in SH-SY5Y human neuroblastoma cell line exposed to Aß1-42 and to explore some mechanisms that underlie netrin-1 effects. Cultured SH-SY5Y neuroblast-like cells were treated with netrin-1 prior to Aß1-42 exposure and the effects were assessed by MTT and ELISA assay kits. Netrin- 1 pretreatment of Aß1-42-exposed SH-SY5Y human neuroblastoma cells attenuated Aß1-42 induced toxic effects, increased cell viability and partially restored levels of 3 inflammatory and oxidative stress biomarkers including: nuclear factor erythroid 2-like 2 (Nrf2), tumor necrosis factor alpha (TNFα) and nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB). Based on the findings of this study, netrin-1 represents a promising therapeutic bio agent to abrogate cellular inflammation and reactive oxygen species (ROS) activation induced by Aß1-42 in the SH-SY5Y cell model of AD.

Protagonist Role of Opioidergic System on Post-Traumatic Stress Disorder and Associated Pain.

OBJECTIVE: Post-traumatic stress disorder (PTSD) and chronic pain often co-occur. Studies have shown an interaction between pain and PTSD. In this narrative review, we aim to support conducting comprehensive studies by describing PTSD, pain and determining whether opioidergic system, its agonist and antagonist manipulation could positively or negatively affect PTSD symptoms and concurrent pain. METHODS: Term searches was done in Google Scholar, Scopus, ScienceDirect, Web of Science and PubMed databases as well as hand searching in key resource journals from 1979-2019. RESULTS: There are a lot of contradictions and disputes when endogenous opioidergic system and opioidergic antagonist system are studied in PTSD patients. Exogenous morphine administration in PTSD patients can decrease the symptoms of PTSD but it doesn't have a pain reduction effect to an acceptable level. Beta-endorphin as an endogenous opioid is effective in pain reduction in the moment of events but after minutes to hours, the endorphins withdrawal syndrome leads to exaggerated intrusive thoughts and flashbacks of PTSD, which exacerbate the pain. It has also been shown that naloxone, as an opioidergic antagonist, can reduce or increase the PTSD symptoms and its associated pain. CONCLUSION: Data suggest different roles of opioidergic system and their antagonist in pain control and mood in PTSD. However, further investigations need to be done in order to reveal the role of endogenous opioidergic system and opioidergic antagonist system as a mediator in PTSD patients suffering from acute or chronic pain.