Curcumin-ZnO conjugated nanoparticles confer neuroprotection against ketamine-induced neurotoxicity.

BACKGROUND: Nanotechnology and its application to manipulate herbal compounds to design new neuroprotective agents to manage neurotoxicity has recently increased. Cur-ZnO conjugated nanoparticles were synthesized and used in an experimental model of ketamine-induced neurotoxicity. METHODS: Cur-ZnO conjugated nanoparticles were chemically characterized, and the average crystalline size was determined. Forty-nine adult mice were divided into seven groups of seven animals each. Normal saline was given to control mice (group 1). Ketamine (25 mg/kg) was given to a second group. A third group of mice was given ketamine (25 mg/kg) in combination with curcumin (40 mg/kg), while mice in groups 4, 5, and 6 received ketamine (25 mg/kg) plus Cur-ZnO nanoparticles (10, 20, and 40 mg/kg). Group 7 received only ZnO (5 mg/kg). All doses were ip for 14 days. Hippocampal mitochondrial quadruple complex enzymes, oxidative stress, inflammation, and apoptotic characteristics were assessed. RESULTS: Cur-ZnO nanoparticles and curcumin decreased lipid peroxidation, GSSG content, IL-1ß, TNF-α, and Bax levels while increasing GSH and antioxidant enzymes like GPx, GR, and SOD while increasing Bcl-2 level and mitochondrial quadruple complex enzymes in ketamine treatment groups. CONCLUSION: The neuroprotective properties of Cur-ZnO nanoparticles were efficient in preventing ketamine-induced neurotoxicity in the mouse brain. The nanoparticle form of curcumin (Cur-ZnO) required lower doses to produce neuroprotective effects against ketamine-induced toxicity than conventional curcumin.

Neuropathies and neurological dysfunction induced by coronaviruses.

During the recent years, viral epidemic due to coronaviruses, such as SARS (Severe Acute Respiratory Syndrome), Middle East Respiratory Coronavirus Syndrome (MERS), and COVID-19 (coronavirus disese-19), has become a global problem. In addition to causing cardiovascular and respiratory lethal dysfunction, these viruses can cause neurodegeneration leading to neurological disorders. Review of the current scientific literature reveals the multiple neuropathies and neuronal dysfunction associated with these viruses. Here, we review the major findings of these studies and discuss the main neurological sequels and outcomes of coronavirus infections with SARS, MERS, and COVID-19. This article analyzes and discusses the main mechanisms of coronavirus-induced neurodegeneration according to the current experimental and clinical studies. Coronaviruses can damage the nerves directly through endovascular dysfunctions thereby affecting nerve structures and synaptic connections. Coronaviruses can also induce neural cell degeneration indirectly via mitochondrial dysfunction inducing oxidative stress, inflammation, and apoptosis. Thus, coronaviruses can cause neurological disorders by inducing neurovascular dysfunction affecting nerve structures and synaptic connections, and by inducing inflammation, oxidative stress, and apoptosis. While some of these mechanisms are similar to other RNA viruses, the neurotoxic mechanisms of COVID-19, MERS, and SARS-CoV viruses are unknown and need detailed clinical and experimental studies.

Novel Neuroprotective Potential of Crocin in Neurodegenerative Disorders: An Illustrated Mechanistic Review.

Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Recent studies reported that crocin, a carotenoid chemical compound common in crocus and gardenia flowers, has protective effects in neurodegenerative disorders due to its anti-oxidative, anti-inflammatory, and anti-apoptotic properties in the nervous system. This article reviews the new experimental, clinical, and pharmacological studies on the neuroprotective properties of crocin and its potential mechanisms to modulate metabolic oxidative stress and inflammation in neurodegenerative disorders.

Noscapine protects the H9c2 cardiomyocytes of rats against oxygen-glucose deprivation/reperfusion injury.

Noscapine is an antitumor alkaloid derived from Papaver somniferum plants. Our previous study has demonstrated that exposure of noscapine on primary murine fetal cortical neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R) has neuroprotective effects. In current study, the effects of noscapine on cardiomyocytes (H9c2 cells) damage caused by 120 minutes (min) of OGD/R were evaluated and we determined whether the addition of BD1047, sigma-one receptor antagonist, prevents the protective effects of noscapine in H9c2 cells through the production of nitric oxide (NO) and apoptosis. To initiate OGD, H9c2 cells was transferred to glucose-free DMEM, and placed in a humidified incubation chamber. Cell viability was assessed with noscapine (1-5 µM) in the presence or absence of BD1047, 24 hours (h) after OGD/R. Cell viability, NO production and apoptosis ratio were evaluated by the MTT assay, the Griess method and the quantitative real-time PCR. Noscapine considerably improved the survival of H9c2 cells compared to OGD/R. Also, noscapine was extremely capable of reducing the concentrations of NO and Bax/Bcl-2 ratio expression. While the BD1047 administration alone diminished cell viability and increased the Bax/Bcl-2 ratio and NO levels. The addition of noscapine in the presence of BD1047 did not increase the cell viability relative to noscapine alone. Noscapine exerted cardioprotective effects exposed to OGD/R-induced injury in H9c2 cells, at least partly via attenuation of NO production and Bax/Bcl-2 ratio, which indicates that the sigma-one receptor activation is involved in the protection by noscapine of H9c2 cells injured by OGD/R.

Acceptance or Rejection of the COVID-19 Vaccine: A Study on Iranian People's Opinions toward the COVID-19 Vaccine.

We aimed to assess the Iranian people's attitude and confidence in the COVID-19 vaccine, their concerns about the safety of vaccines, and their reasons for accepting or rejecting the COVID-19 vaccine. We conducted a web-based cross-sectional study with a mixed qualitative−quantitative approach from December 2020 to February 2021. Our questionnaire consisted of a COVID-19 vaccine attitude questionnaire, a COVID-19 vaccine confidence inventory, a modified vaccine safety scale, and questions about participants' decision to accept or refuse the COVID-19 vaccine, and their explanations for their decisions. The research included 1928 people with an average age of 34.88 years with 1236 (64.1%) being female. A total of 1330 participants desired to have the COVID-19 vaccine (69%). Female gender, lower educational levels, following COVID-19 news through sources other than websites and social media, not following COVID-19 news, and loss of a first-degree relative due to COVID-19 were all associated with a more negative attitude toward the COVID-19 vaccine (p < 0.01). To conclude, the acceptance rate of the COVID-19 vaccine among Iranians is comparable to the international average; however, it is still unfavorable. There are serious challenges to the vaccination program in Iran, such as older adults' lower intention to undergo the COVID-19 vaccine and misinformation.

The possible role of CREB-BDNF signaling pathway in neuroprotective effects of minocycline against alcohol-induced neurodegeneration: molecular and behavioral evidences.

Abuse of alcohol triggers neurodegeneration in human brain. Minocycline has characteristics conferring neuroprotection. Current study evaluates the role of the CREB-BDNF signaling pathway in mediating minocycline's neuroprotective effects against alcohol-induced neurodegeneration. Seventy adult male rats were randomly split into groups 1 and 2 that received saline and alcohol (2 g/kg/day by gavage, once daily), respectively, and groups 3, 4, 5, and 6 were treated simultaneously with alcohol and minocycline (10, 20, 30 and 40 mg/kg I.P, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. Morris water maze (MWM) has been used to assess cognitive activity. Hippocampal neurodegenerative and histological parameters as well as cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were assessed. Alcohol impaired cognition, and concurrent therapy with various minocycline doses attenuated alcohol-induced cognition disturbances. Additionally, alcohol administration boosted lipid peroxidation and levels of glutathione in oxidized form (GSSG), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and Bax protein, while decreased reducing type of glutathione (GSH), Bcl-2 protein, phosphorylated CREB, and BDNF levels in rat hippocampus. Alcohol also decreased the activity in the hippocampus of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). In comparison, minocycline attenuated alcohol-induced neurodegeneration; elevating expression levels of P-CREB and BDNF and inhibited alcohol induced histopathological changes in both dentate gyrus (DG) and CA1 of hippocampus. Thus, minocycline is likely to provide neuroprotection against alcohol-induced neurodegeneration through mediation of the P-CREB/BDNF signaling pathway.

Curcumin Can be Acts as Effective agent for Prevent or Treatment of Alcohol-induced Toxicity in Hepatocytes: An Illustrated Mechanistic Review.

Previous studies have shown that alcohol abuse can cause serious liver damage and cirrhosis. The main pathway for these types of hepatocellular cell neurodegeneration is mitochondrial dysfunction, which causes lipid peroxidation and dysfunction of the glutathione ring and the defect of antioxidant enzymes in alcoholic hepatic cells. Alcohol can also initiate malicious inflammatory pathways and trigger the initiation and activation of intestinal and extrinsic apoptosis pathways in hepatocellular tissues that lead to cirrhosis. Previous studies have shown that curcumin may inhibit lipid peroxidation, glutathione dysfunction and restore antioxidant enzymes. Curcumin also modulates inflammation and the production of alcohol-induced biomarkers. Curcumin has been shown to play a critical role in the survival of alcoholic hepatocellular tissue. It has been shown that curcumin can induce and trigger mitochondrial biogenesis and, by this mechanism, prevent the occurrence of both intrinsic and extrinsic apoptosis pathways in liver cells that have been impaired by alcohol. According to this mechanism, curcumin may protect hepatocellular tissue from alcohol-induced cell degeneration and may therefore survive alcoholic hepatocellular tissue. . Based on these mechanisms, the protective functions of curcumin against alcohol-induced cell degeneration due to oxidative stress, inflammation, and apoptosis events in hepatocellular tissue have been recorded. Hence, in this research, we have attempted to evaluate and analyze the main contribution mechanism of curcumin cell defense properties against alcohol-induced hepatocellular damage, according to previous experimental and clinical studies, and in this way we report findings from major studies.

Pharmacological and Molecular Evidence of Neuroprotective Curcumin Effects Against Biochemical and Behavioral Sequels Caused by Methamphetamine: Possible Function of CREB-BDNF Signaling Pathway.

INTRODUCTION: The neuroprotective impact of curcumin and the role of CREB (Cyclic AMP Response Element Binding protein)-BDNF (Brain-Derived Neurotrophic Factor) signaling pathway was evaluated in Methamphetamine (METH)-induced neurodegeneration in rats. METHODS: Sixty adult male rats were randomly divided into 6 groups. While normal saline and 10 mg/kg METH were administered intraperitoneally in groups 1 and 2, groups 3, 4, 5, and 6 received METH (10 mg/kg) and curcumin (10, 20, 40, and 80 mg/kg, respectively) simultaneously. Morris water maze test was administered, and oxidative hippocampal, antioxidant, inflammatory, apoptotic, and CREB and BDNF were assessed. RESULTS: We found that METH disturbs learning and memory. Concurrent curcumin therapy (40 and 80 mg/kg) decreased cognitive disturbance caused by METH. Multiple parameters, such as lipid peroxidation, the oxidized form of glutathione, interleukin 1 beta, tumor necrosis factor-alpha, and Bax were increased by METH therapy, while the reduced type of glutathione, Bcl-2, P-CREB, and BDNF concentrations in the hippocampus were decreased. CONCLUSION: Different doses of curcumin adversely attenuated METH-induced apoptosis, oxidative stress, and inflammation but enhanced the concentrations of P-CREB and BDNF. The neuroprotection caused by curcumin against METH-induced neurodegeneration is mediated through P-CREB-BDNF signaling pathway activation.

Interaction of high-intensity endurance exercise and nandrolone on cardiac remodeling: role of adipo-cardiac axis.

OBJECTIVES: Given the cardiac pathological remodeling following to anabolic androgenic steroids (AASs) consumption, we examined the effect of chronic administration of nandrolone decanoate with high-intensity endurance exercise on the left ventricular hypertrophy index, levels of hydroxyproline, tumor necrosis factor-alpha (TNF-α), adiponectin (APN) and its receptors (AdipoR1 and AdipoR2) expression in rats' hearts. METHODS: The male Wistar rats randomly divided to six groups included the control (CTL), exercise (Ex), nandrolone (Nan), vehicle (Arach), trained vehicle (Ex + Arach), and trained nandrolone (Ex + Nan) groups that were treated for eight weeks. RESULTS: Nandrolone consumption significantly enhanced the hypertrophy index (p<0.05) and exercise intensified this effect. It also increased the level of cardiac hydroxyproline (p<0.001), however exercise completely masked this effect. The values of TNF-α protein and AdipoR1 protein significantly increased in trained nandrolone-treated (Ex + Nan) group in comparison with CTL group (p<0.05), however, did not show significant alteration in Nan or Ex groups. High-intensity endurance exercise significantly enhanced the AdipoR2 protein (p<0.05), but, co-administration of nandrolone with exercise prevented this effect. The mRNA expression of AdipoR1 significantly reduced in the animals that received nandrolone for eight weeks and exercise recovered this effect (p<0.001). CONCLUSIONS: Despite an additive effect of high-intensity endurance exercise plus nandrolone on TNF-α level, their effects on hydroxyproline and APN receptors expression is incompatible in heart of rat. It is suggests a part of beneficial regulatory role of endurance exercise against nandrolone induced heart remodeling may apply through modulation of APN system.

Molecular, histological and behavioral evidences for neuroprotective effects of minocycline against nicotine-induced neurodegeneration and cognition impairment: Possible role of CREB-BDNF signaling pathway.

AIM: Neurodegeneration is one of the serious adverse effects of stimulant agents such as nicotine. Minocycline possess established neuroprotective properties. The role of CREB-BDNF signaling pathway in mediating the neuroprotective effects of minocycline against nicotine-induced neurodegeneration in rats was evaluated in current study. METHODS: Seventy adult male rats were divided randomly into seven groups. Group 1 and 2, received 0.7 ml/rat of normal saline (i.p) and nicotine (10 mg/kg, s.c) respectively. Groups 3, 4, 5 and 6, treated concurrently with nicotine (10 mg/kg) and minocycline (10, 20, 30 and 40 mg/kg, i.p, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. From 17th to 21 st days of experiment, Morris water maze (MWM) was used to evaluate learning and spatial memory in rats treated in different groups. According to the critical role of hippocampus in cognitive behavior, hippocampal neurodegenerative parameters (oxidative stress and inflammatory biomarkers) and also cyclic AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were evaluated in isolated hippocampus in day 22 of experiment and after drug treatment. Also hippocampal cell density and tissue changes were evaluated by hematoxylin and eosin staining. RESULT: Nicotine administration impaired the learning and spatial memory in rats and simultaneous treatment with various doses of minocycline attenuated the nicotine-induced cognition disturbances. In addition, nicotine treatment increased lipid peroxidation and the levels of oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and Bax protein, while decreasing reduced form of glutathione (GSH), Bcl-2 protein, P-CREB and BDNF levels in the hippocampus of experimental animals. Nicotine also reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) in the hippocampus. Minocycline attenuated nicotine-induced neurodegeneration and elevating CREB (both forms) and BDNF levels. Also minocycline treatment alone increases the cognitive activity and increased CREB (both forms) and BDNF levels and decreased oxidative stress, inflammation and apoptotic biomarkers. Minocycline at high doses cause inhibition of nicotine induced cell density and changes in both area of dentate gyrus (DG) and CA1 in hippocampus. CONCLUSION: It can be concluded that minocycline, probably through activation of P-CREB/BDNF signaling pathway, confers neuroprotection against nicotine-induced neurodegeneration in rat hippocampus.

Neuroprotective and neuro-survival properties of safinamide against methamphetamine-induced neurodegeneration: Hypothetic possible role of BDNF/TrkB/PGC-1α signaling pathway and mitochondrial uncoupling protein -2(UCP-2).

Methamphetamine is a behavioral psychostimulant that has a high potential for misuse and induction of neurotoxicity. Safinamide is a novel inhibitor of monoamine oxidase B (MAOB) with neuroprotective properties. Methamphetamine abuse causes dysfunction in the respiratory chain of the mitochondria, but the specific signaling mechanism and role of the uncoupling protein-2(UCP-2) remain unclear. As we know, some indirect evidence indicates that neurodegeneration can be caused by inhibition of the brain-derived neurotrophic factor (BDNF) receptor, TrkB and its downstream signaling pathway, such as the PGC-1α protein. Neuroprotective strategies and approaches to the management, treatment or prevention of methamphetamine-induced neurodegeneration by modulating BDNF / TrkB / PGC-1α-UCP-2 can be considered as novel therapeutic approaches to these psychostimulant neurochemical and neurobehavioral approaches. Previous studies have shown that safinamide, a monoamine oxidase-B (MAOB) inhibitor, can function as a neuroprotective agent and inhibit the neurodegenerative process especially in Parkinson's disease but its impact on other neurodegenerative processes and drug-induced neurotoxicity remain unclear. Although there is some evidence that BDNF / TrkB / PGC-1α-UCP-2 signaling pathway and mitochondrial UCP-2 mediated safinamide induced neuroprotection but it's exact and precise mechanism of action and neuroprotective effects in neurodegenerative disorder and the protective properties against methamphetamine induced neurodegeneration and the role of BDNF / TrkB / PGC-1α signaling pathway and role of mitochondrial UCP-2 in this process have not yet been clarified. Therefore, in subjects addicted to methamphetamine, we hypothesized that safinamide will provide neuroprotection against methamphetamine-prompted neurodegeneration, and it appears that BDNF / TrkB / PGC-1α signaling pathway and mitochondrial UCP-2 are likely to play a critical role.

Novel Insight to Neuroprotective Potential of Curcumin: A Mechanistic Review of Possible Involvement of Mitochondrial Biogenesis and PI3/Akt/ GSK3 or PI3/Akt/CREB/BDNF Signaling Pathways.

Neurodegeneration is a gradual mechanism of neuronal loss arising from numerous cellular and molecular events such as mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis, and the consequence of these processes is neuroplasticity impairment, cognitive diseases, mood-related diseases, and normal cellular activity. Over the last year, major advances have been made in the field of the introduction of herbal compounds with neuroprotective efficacy, one of which is curcumin. Curcumin (diferuloylmethane) is the most abundant turmeric component extracted from the Curcuma longa plant rhizomes. Accumulating evidence indicates that curcumin may induce mitochondrial biogenesis and can function as an antioxidant, anti-inflammatory, and anti-apoptotic agent, which may be used effectively to treat chronic neurodegenerative diseases and any situation in which the neurodegeneration process takes place. Curcumin has been shown to play a critical role in activating two essential signaling pathways phosphatidylinositol-3(PI3)/ protein kinase B(Akt)/ glycogen synthase kinase-3 (GSK3) and PI3/Akt/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) and preventing the incidence of neurodegeneration via these two pathways. Curcumin's protective functions against neural cell degeneration due to mitochondrial dysfunction and consequent events such as oxidative stress, inflammation, and apoptosis in neural cells have been documented and clinical data have increased to suggest that curcumin may be a standard candidate as a neuroprotective agent. Therefore, in this review, we summarized the clinical and experimental studies and interpreted the key contributory mechanisms of neuroprotective properties of curcumin in neurodegenerative diseases and disorders. We also tried to understand the function of PI3/Akt/GSK3 and PI3/Akt/CREB/BDNF signaling pathways in the neuroprotective properties of curcumin and tried to evaluate their association with antioxidant, anti-inflammatory, anti-apoptosis and biogenesis effects of mitochondria.

New nanoprobe for breast cancer cell imaging based on low-density lipoprotein.

Many malignant cancers have an increased demand for lipoprotein due to the requirement for lipids for the rapid proliferation of the tumours and which is met by the increased availability of LDL through upregulation of LDL transporters. This unique phenomenon is the basis for the use of LDL based nanoparticles for cell imaging. In this study, a novel MR-active LDL nanoparticle was synthesised as the MRI probes. This MR-active LDL was characterised by using different techniques including scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier-transform infra-red spectroscopy (FTIR) and magnetic resonance imaging (MRI). The intracellular uptake of Gd3+ and cytotoxicity was measured by ICP-AES and MTT assay respectively. Results suggest that this nanoprobe with spherical shape and size of 55 nm has reduced relaxation time compared to commercial contrast agent and is introduced as an appropriate imaging probe. The amount of reabsorption of nanoprobe increased up to 6 h and given that the connection of the chelator does not have an effect on reabsorption proves that entry through transporter of APO section has done. This study lays the basis for exploring a personalised medicine strategy by directing a patient's own LDL to cancer cell imaging in the early stages.

Pharmacological Evidences for Curcumin Neuroprotective Effects against Lead-Induced Neurodegeneration: Possible Role of Akt/GSK3 Signaling Pathway.

One of main herbal compounds with neuroprotective effects is curcumin. Lead poisoning cause neurodegeneration effect but its clear mechanism remains unknown. The current study evaluates the role of Akt/GSK3 signaling pathway in mediating the neuroprotective effects of curcumin against lead -induced neurodegeneration in rats. Sixty adult male rats were divided to: Group 1 and 2 receiving normal saline and drinking water containing 0.075% of lead acetate. Groups 3, 4, 5, and 6 were treated concurrently with lead acetate (0.075% in drinking water) and Curcumin (10, 20, 40, and 80 mg/kg I.P, respectively). Morris water maze (MWM) was used to evaluate cognitive activity, Hippocampal oxidative, anti-oxidant, as well as inflammatory and apoptotic factors and also Akt and GSK3 protein levels were studied. We found that lead poisoning disturbed the learning and memory and simultaneous treatment with Curcumin reduced the lead -induced cognition disturbances. In addition, lead acetate treatment increased lipid peroxidation and the levels of IL-1ß, TNF-α , Bax, GSK3 (total and phosphorylated) while reducing reduced form of GSH, Bcl-2, and Akt3 (total and phosphorylated) levels in the hippocampus. Lead also reduced the activity of SOD, GPx, and GR in the hippocampus. In contrast, various doses of Curcumin attenuated lead -induced apoptosis, oxidative stress and inflammation; while elevating P-Akt and reduced of GSK3 levels. Thus, Curcumin via mediation of Akt/GSK3 signaling pathway confers neuroprotection against lead-induced neurodegeneration in hippocampus.

Selegiline acts as neuroprotective agent against methamphetamine-prompted mood and cognitive related behavior and neurotoxicity in rats: Involvement of CREB/BDNF and Akt/GSK3 signal pathways.

OBJECTIVES: Present study investigated the neuroprotective effects of selegiline and the molecular mechanisms involved in methamphetamine-induced neurotoxicity. MATERIALS AND METHODS: Male wistar rats were randomly divided into six groups (10 rats in each group). Group 1 and group 2 received normal saline and methamphetamine (10 mg/kg), respectively. Groups 3, 4, 5 and 6 were treated simultaneously with methamphetamine and selegiline. From day 22 to day 28, forced swim test, elevated plus maze, and open field test were conducted to assess mood (anxiety and depression) levels, and from day 17 to day 21, Morris Water Maze was conducted for cognition assessment. On day 29, hippocampus of the animals were isolated and evaluated by ELISA method for oxidative, antioxidant, and inflammatory factors and expression levels of active (total) and inactive (phosphorylated) forms of cyclic AMP response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), Akt (Protein Kinase B) and glycogen synthase kinase 3 (GSK3) proteins. RESULTS: Selegiline reduced behavioral impacts caused by methamphetamine in all doses. Methamphetamine administration may improve malondialdehyde, tumor necrosis factor-alpha, interleukin-1 beta and GSK3 (both forms). Moreover, methamphetamine reduced the activity of superoxide dismutase, glutathione peroxidase, glutathione reductase, amount of BDNF, CREB and Akt (both forms). CONCLUSION: Current research showed that selegiline can protect the brain from methamphetamine-prompted neurodegeneration, and this could be intervened by CREB -BDNF or Akt-GSK3 signaling pathways.

Crocin may be useful to prevent or treatment of alcohol induced neurodegeneration and neurobehavioral sequels via modulation of CREB/BDNF and Akt/GSK signaling pathway.

The neurodegeneration and neurobehavioral consequences of alcohol are serious and offering therapeutic approaches for management of these types of neurodegeneration is one of the main concerns of researchers in this manner. Alcohol-stimulated oxidative stress, apoptosis and inflammation, with modulation of involved signaling pathway in neuroprotection, was reported previously. Neuroprotective strategy for management of alcohol induced neurodegeneration through a new generation neuroprotective agent and based on modulation of some neuroprotective signaling pathway such as CREB/BDNF and Akt/GSK has always been superior to any other therapeutic interventions. Therefore, the introduction and development of potential new neuroprotective properties and clarification of their effects on major cell signaling such as CREB/BDNF and Akt/GSK is necessitated. During recent years, using new neuroprotective compounds with therapeutic probability for treatment of alcohol induced neuro-biochemical and neuro-behavioral malicious effects have been amazingly increased. Many previous studies have reported the neuroprotective roles of crocin (major active component of saffron) in multiple neurodegenerative events and diseases in animal model. But the role of crocin neuroprotective effects against alcohol induced neurodegeneration and neurobehavioral sequels and also role of CREB/BDNF and Akt/GSK in this manner remain unclear. Hence we hypothesized that by using crocin in alcohol dependent subject it would provide neuroprotection against alcohol induced neurodegeneration and neurobehavioral and probably can manage sequels of alcohol abuses. Also we hypothesized that crocin, via intonation of CREB/BDNF and Akt/GSK signaling pathway, can inhibit alcohol induced neurodegeneration. In this article, we tried to discuss our hypothesis regarding the possible role of crocin, as a potent neuroprotective agent, and also role of Akt/GSK and CREB/BDNF signaling pathway in treatment of alcohol induced neurodegeneration and neurobehavioral through its anti-inflammatory,anti-apoptotic, anti-oxidative stress and cognitive enhancer.

Cannabinoids Δ9-tetrahydrocannabinol and cannabidiol may be effective against methamphetamine induced mitochondrial dysfunction and inflammation by modulation of Toll-like type-4(Toll-like 4) receptors and NF-κB signaling.

The neurodegeneration, neuro-inflammation and mitochondrial dysfunction which occur by methamphetamine (METH) abuse or administration are serious and motivation therapeutic approaches for inhibition of these types of neurodegeneration. As we know, METH through Toll-like receptors (TLRs), specially type 4, and NF-κB signaling pathway causes neuro-inflammation and mitochondrial dysfunction. Neuroprotective approach for management of METH-induced neurodegeneration, inflammation and mitochondrial dysfunction, through a novel neuroprotective agent is continuously being superior to any kind of other therapeutic strategy. Therefore, the clarification, introduction and development of efficacious novel neuroprotective agent are demanded. During recent years, using new neuroprotective agent with therapeutic probability for treatment of METH-induced neuro-inflammation and mitochondrial dysfunction has been astoundingly increased. Previous studies have stated the neuroprotective and anti-inflammatory roles ofcannabinoid derivate such as cannabidiol (CBD) and delta-9-tetrahydrocannabinol (Δ9-THC) in multiple neurodegenerative events and diseases. According to literature cannabinoid derivate, by inhibition of TLR4 and activation of NF-κB signaling pathway, exerts their anti-inflammatory and neuroprotective effects and cause mitochondrial biogenesis. Thus we hypothesized that by using cannabinoids in METH dependent subject it would provide neuroprotection against METH-induced neurodegeneration, neuro-inflammation and mitochondrial dysfunction and probably can manage sequels of METH-induced neurochemical abuses via modulation of TLR4/NF-κB signaling pathway. In this article, we tried to discuss our hypothesis regarding the possible role of CBD and Δ9-THC, as a potent neuroprotective and anti-inflammatory agents, in inhibition or treatment of METH-induced neurodegeneration, neuro-inflammation and mitochondrial dysfunction through its effects on TLR4/NF-κB signaling pathway.

Crocin acts as a neuroprotective mediator against methylphenidate­induced neurobehavioral and neurochemical sequelae: Possible role of the CREB-BDNF signaling pathway.

Methylphenidate (MPH) abuse causes adverse neurobehavioral and neurochemical effects. Some herbal components such as crocin have shown neuroprotective properties. The current study evaluates the potential role of the cyclic AMP response element binding protein (CREB)­brain­derived neurotrophic factor (BDNF) signaling pathway in mediating the neuroprotective effects of crocin against MPH­induced neurotoxicity in rats. Seventy adult male rats were randomly divided into seven groups. Group 1 and 2 received 0.7 ml/rat of normal saline and 10 mg/kg of MPH, respectively. Groups 3, 4, 5, and 6 were treated simultaneously with MPH (10 mg/kg) and crocin (10, 20, 40, and 80 mg/kg, respectively) for 21 days. Group 7 was treated with crocin (80 mg/kg) alone for 21 days. The Morris water maze (MWM) and open field test were used to assess cognitive and locomotor activities. Hippocampal neurotoxicity parameters and levels of BDNF and CREB were evaluated. Simultaneous treatment with various doses of crocin reduced the MPH­induced cognition disturbances and hyperlocomotion. In addition, lipid peroxidation increased with MPH treatment and levels of the oxidized forms of glutathione (GSSG), interleukin 1 beta (IL­1ß), tumor necrosis factor alpha (TNF­α), and Bax increased. MPH treatment decreased levels of the reduced form of glutathione (GSH), P­CREB, Bcl­2, and BDNF in the hippocampus. MPH also reduced activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase in the hippocampus. In contrast, crocin attenuated MPH­induced oxidative stress, inflammation, and apoptosis, and increased levels of P­CREB and BDNF. Thus, crocin - likely via stimulation of the P­CREB/BDNF signaling pathway - displayed neuroprotection against MPH­induced neurotoxicity.

A hypothetic role of minocycline as a neuroprotective agent against methylphenidate-induced neuronal mitochondrial dysfunction and tau protein hyper-phosphorylation: Possible role of PI3/Akt/GSK3ß signaling pathway.

The underlining mechanism in neural mitochondrial dysfunction and consequences neurotoxicity, and cognitive behavior after methylphenidate (MPH) prolonged uses is unclear and proposing of therapeutic approaches for treatment of these types of neurotoxicity is one of the main goals of scientist in this manner. MPH-induced mitochondrial dysfunction in neural cells caused induction of oxidative stress, apoptosis, inflammation and cognition impairment, which leads to neurotoxicity, was reported previously but role of key neural cells proteins and involved signaling pathway in this manner remained indeterminate. Tau protein aggregation is a biomarker for mitochondrial dysfunction, neurodegenerative event and cognition impairment. Tau aggregation occur by stimulation effects of Glycogen synthase kinase-3(GSK3ß) and phosphatidylinositol 3-kinase (PI3K) which activates protein kinase B(Akt) and causes inhibition of phosphorylation(activation) of GSK3ß, thus Akt activation can cause inhibition of tau aggregation (hyper-phosphorylation). Management of mentioned MPH-induced mitochondrial dysfunction and consequences of neurotoxicity, and cognitive behavior through a new generation neuroprotective combination, based on modulation of disturbed in Akt function and inhibition of GSK3ß and tau hyper-phosphorylation can be a prefect therapeutic interventions. Therefore, finding, introduction and development of new neuroprotective properties and explanation of their effects with potential capacity for modulation of tau hyper-phosphorylation via PI3/Akt/GSK signaling pathway is necessitated. During recent years, using new neuroprotective compounds with therapeutic probability for treatment of psychostimulant-induced mitochondrial dysfunction, neurotoxicity and cognitive malicious effects have been amazingly increased. Many previous studies have reported the neuroprotective roles of minocycline (a broad-spectrum and long-acting antibiotic) in multiple neurodegenerative events and diseases in animal model. But the role of neuroprotective effects of this agent against MPH induced mitochondrial dysfunction, neurotoxicity and cognitive malicious and also role of tau hyper-phosphorylation by modulation of PI3/Akt/GSK signaling pathway in this manner remain unknown. Thus we suggested and theorized that by using minocycline in MPH addicted subject, it would provide neuroprotection against MPH-induced mitochondrial dysfunction, neurotoxicity and cognitive malicious. Also we hypothesized that minocycline, via modulation of PI3/Akt/GSK and inhibition of tau hyper-phosphorylation, can inhibit MPH-induced mitochondrial dysfunction, neurotoxicity and cognitive malicious. In this article, we tried to discuss our hypothesis regarding the possible role of minocycline, as a powerful neuroprotective agent, and also role of tau hyper-phosphorylation related to PI3/Akt/GSK signaling pathway in treatment of MPH-induced mitochondrial dysfunction, neurotoxicity and cognitive disturbance.

Acute Toxicity Evaluation of Glycosylated Gd3+-Based Silica Nanoprobe.

PURPOSE: Early stage diseases diagnosed using magnetic resonance imaging (MRI) techniques is of high global interest as a potent noninvasive modality. MRI contrast agents are improved through modifications in structural and physicochemical properties of the applied nanoprobes. But, the potential toxic effects of nanoprobes upon exposure to biological systems are still a major concern. PROCEDURE: In this study, the acute toxicity of glycosylated Gd3+-based silica mesoporous nanospheres (GSNs) as a MRI contrast agent was evaluated in Balb/c mice. In order to evaluate in vivo toxicity of GSN, preclinical studies, daily weight monitoring, hematological/blood chemistry tests, and histological assessment were conducted. Magnetic resonance relaxivities of GSN was determined using a MRI scanner. RESULTS: The obtained results suggest that in vivo toxicity of GSN was mostly influenced by nanoparticle surface area, functionality, and nanoparticle zeta potential. The maximum tolerated dose (MTD) increased in the following order: mesoporous silica nanospheres (MSNs) at 1 mg/mice < GSN (aspect ratio 1, 2, 8) at 40 mg/mice. The results also indicate GSN, one of the best cell imaging contrast agent, which does not show any significant toxicity on multiple vital organs following injection of 20 mg/mice, while a significant T1-weighted enhancement was observed in whole body of a Balb/c mice 15 min postinjection of (5 µmol/kg) of body weight of GSN. CONCLUSIONS: These results shed light on the functionality of MSNs to minimize in vivo toxicity. Also, glyconanoprobe can be beneficially used for nanomedicine and cellular imaging applications without any significant toxicity.