Memory loss induced by lisdexamfetamine in the rat: A behavioral, electrophysiological, and histopathological Study.

Lisdexamfetamine (LDX) is one of the drugs commonly used to treat attention deficit hyperactivity disorder (ADHD). However, its neurological side effects, particularly on cognition, are not fully understood. The present study focused on memory in rats treated with four weeks of LDX injection. We compared LDX-treated rats with control ones, using several methods to evaluate the behavioral responses and electrophysiological, molecular, and histological properties in the hippocampus. Our findings demonstrated that subchronic administration of LDX impaired behavioral performance in all memory assessment tests (Y maze, Morris Water Maze, and Shuttle box). Although LDX did not alter population spike (PS) amplitude, it increased the field excitatory postsynaptic potential (fEPSP) slope of evoked potentials of LTP components. Also, in addition to an increase in expression of caspase-3 in the hippocampus, which indicates the susceptibility to apoptosis in LDX-treated rats, the number of microglia and astrocytes went up significantly in the LDX group. Moreover, Sholl's analysis showed an increase in the soma size and total process length in both hippocampal astrocytes and microglia. Overall, because of these destructive effects of LDX on the hippocampus, which is one of the critical memory-related areas of the brain, the findings of this investigation provide evidence to show the disruption of memory-related variables following the LDX. However, more research is needed to clarify it.

The elderberry diet protection against intrahippocampal Aß-induced memory dysfunction; the abrogated apoptosis and neuroinflammation.

This study evaluates whether elderberry (EB) effectively decreases the inflammation and oxidative stress in the brain cells to reduce Aß toxicity. In the Aß + EB group, EB powder was added to rats' routine diet for eight consecutive weeks. Then, spatial memory, working memory, and long-term memory, were measured using the Morris water maze, T-maze, and passive avoidance test. Also, in this investigation immunohistopathology, distribution of hippocampal cells, and gene expression was carried out. Voronoi tessellation method was used to estimate the spatial distribution of the cells in the hippocampus. In addition to improving the memory functions of rats with Aß toxicity, a reduction in astrogliosis and astrocytes process length and the number of branches and intersections distal to the soma was observed in their hippocampus compared to the control group. Further analysis indicated that the EB diet decreased the caspase-3 expression in the hippocampus of rats with Aß toxicity. Also, EB protected hippocampal pyramidal neurons against Aß toxicity and improved the spatial distribution of the hippocampal neurons. Moreover, EB decreased the expression of inflammatory and apoptotic genes. Overall, our study suggest that EB can be considered a potent modifier of astrocytes' reactivation and inflammatory responses.

Short chain fatty acids, a possible treatment option for autoimmune diseases.

Gut microbiota can interact with the immune system through its metabolites. Short-chain fatty acids (SCFAs), as one of the most abundant metabolites of the resident gut microbiota play an important role in this crosstalk. SCFAs (acetate, propionate, and butyrate) regulate nearly every type of immune cell in the gut's immune cell repertoire regarding their development and function. SCFAs work through several pathways to impose protection towards colonic health and against local or systemic inflammation. Additionally, SCFAs play a role in the regulation of immune or non-immune pathways that can slow the development of autoimmunity either systematically or in situ. The present study aims to summarize the current knowledge on the immunomodulatory roles of SCFAs and the association between the SCFAs and autoimmune disorders such as celiac disease (CD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), type 1 diabetes (T1D) and other immune-mediated diseases, uncovering a brand-new therapeutic possibility to prevent or treat autoimmunity.

Curcumin attenuates morphine dependence by modulating µ-opioid receptors and glial cell-activated neuroinflammation in rat.

In recent years, the association between neuroinflammation and opioid dependence has attracted considerable attention. Curcumin, a component of the Curcuma longa, has been shown to act as a suppressor of glial cells and inflammatory cytokines. The main goal of this study was to explore the attenuating effects of curcumin on morphine dependence with a focus on neuroinflammation and µ-opioid receptors in the rat prefrontal cortex. To induce morphine dependence in male Wistar rats, morphine was administered i.p. once daily for 18 days in an escalating dose of 10, 20, and 40 mg/kg. Curcumin (2.5, 5, and 10 mg/kg, i.p.) was given from the days 10th to 18th. Immunofluorescence staining and ELISA methods were used to evaluate glial cells activity and inflammatory cytokines levels, respectively. Western blotting was used to evaluate the expression of µ-opioid receptors. The administration of curcumin (2.5, 5, and 10 mg/kg) for 9 days significantly attenuated the symptoms of morphine withdrawal syndrome. The prefrontal cortex concentration of TNF-α and IL-6 was also reduced by curcumin (2.5, 5, and 10 mg/kg) significantly. Furthermore, curcumin decreased the number of Iba1 and GFAP positive cells in morphine-dependent rats. Moreover, the expression of µ-opioid receptors was significantly reduced by curcumin (10 mg/kg). The results of this study demonstrate that curcumin attenuates morphine dependence in rats through an inhibitory effect on neuroinflammation and a decrease in the expression of µ-opioid receptors in the prefrontal cortex.

MicroRNA-140-5p inhibitor attenuates memory impairment induced by amyloid-ß oligomer in vivo possibly through Pin1 regulation.

AIMS: The peptidyl-prolyl cis/trans isomerase, Pin1, has a protective role in age-related neurodegeneration by targeting different phosphorylation sites of tau and the key proteins required to produce Amyloid-ß, which are the well-known molecular signatures of Alzheimer's disease (AD) neuropathology. The direct interaction of miR-140-5p with Pin1 mRNA and its inhibitory role in protein translation has been identified. The main purpose of this study was to investigate the role of miRNA-140-5p inhibition in promoting Pin1 expression and the therapeutic potential of the AntimiR-140-5p in the Aß oligomer (AßO)-induced AD rat model. METHODS: Spatial learning and memory were assessed in the Morris water maze. RT-PCR, western blot, and histological assays were performed on hippocampal samples at various time points after treatments. miRNA-140-5p inhibition enhanced Pin1 and ADAM10 mRNA expressions but has little effect on Pin1 protein level. RESULTS: The miRNA-140-5p inhibitor markedly ameliorated spatial learning and memory deficits induced by AßO, and concomitantly suppressed the mRNA expression of inflammatory mediators TNFα and IL-1ß, and phosphorylation of tau at three key sites (thr231, ser396, and ser404) as well as increased phosphorylated Ser473-Akt. CONCLUSION: According to our results, Antimir-140-mediated improvement of AßO-induced neuronal injury and memory impairment in rats may provide an appropriate rationale for evaluating miR-140-5p inhibitors as a promising agent for the treatment of AD.

Minocycline Improves Memory by Enhancing Hippocampal Synaptic Plasticity and Restoring Antioxidant Enzyme Activity in a Rat Model of Cerebral Ischemia-Reperfusion.

Introduction: Oxidative stress plays a crucial role in the impairment of synaptic plasticity following cerebral ischemia, ultimately resulting in memory dysfunction. Hence, the applying antioxidant agents could be beneficial in managing memory deficits after brain ischemia. Minocycline is a tetracycline antibiotic with antioxidant effect. The main objective of this work was to assess the minocycline effect on the impairment of synaptic plasticity and memory after cerebral ischemia-reperfusion in rats. Methods: Transient occlusion of common carotid arteries was used to induce ischemiareperfusion injury in rats. Single or multiple (once daily for 7 days) dose(s) of minocycline were administered before (pretreatment) or after (treatment) brain ischemia. Seven days after ischemia-reperfusion, passive avoidance performance, long-term hippocampal potentiation, and the activity of antioxidant enzymes were assessed. Results: The passive avoidance test showed that minocycline (20 and 40 mg/kg) significantly increased step-through latency while reducing the duration of staying in a dark chamber in the treatment (but not pretreatment) group. In electrophysiological experiments, the rats treated (but not pretreated) with minocycline (40 mg/kg) showed a significant increase in the amplitude of the field excitatory postsynaptic potentials in the dentate gyrus area of the hippocampus. The treatment (but not pretreatment) with minocycline (20 and 40 mg/kg) resulted in a significant increase in the activity of catalase, glutathione peroxidase, and superoxide dismutase in the hippocampus. Conclusion: It was determined that minocycline attenuates memory dysfunction after cerebral ischemia-reperfusion in rats by improving hippocampal synaptic plasticity and restoring antioxidant enzyme activity. Highlights: Minocycline enhances passive avoidance memory after cerebral ischemia-reperfusion.Minocycline increases enzymatic antioxidant capacity in hippocampal formation.Minocycline improves synaptic plasticity in perforant path-granule cell synapse. Plain Language Summary: Stroke is a common neurological disease with a relatively high mortality rate and disabilities worldwide. More than half of the patients who have had an episode of stroke suffer from the impairment of sensorimotor function and language problems as well as learning and memory disorders. Oxidative stress plays an important role in memory impairment following brain ischemia. Hence, the application of antioxidant agents could be beneficial in managing memory deficits after stroke. Minocycline is a tetracycline antibiotic that is used for the treatment of infectious diseases; it can also function as a potent antioxidant medication. Hence, we hypothesized that minocycline could attenuate memory impairment after brain ischemia. We examined this hypothesis in a rat model of brain ischemia. In this model, the main arteries that supply the brain with oxygenated blood were occluded to induce brain ischemia in the rats. Then, minocycline was administered to the rats, which were subjected to brain ischemia. Seven days later, memory function in the rats was evaluated. The results showed that minocycline could enhance the activity of antioxidant enzymes in the brain, which physiologically fight off oxidative stress. This property of minocycline protects brain cells against ischemic injury and thereby increases the transmission of neuronal signals from one cell to another cell in the memory centers in the brain. These effects ultimately increase the memory function of rats, which was evident in the behavioral memory test. Overall, the study results suggest that minocycline can be considered a memory enhancer drug in patients who suffer from learning and memory disorders following a stroke.

Dopamine D1 Receptor-Mediated Regulation of Per1, Per2, CLOCK, and BMAL1 Expression in the Suprachiasmatic Nucleus in Adult Male Rats.

Photic and non-photic inputs are reported to affect clock gene expressions and behavioral activities in the SCN. However, it is not known whether dopaminergic input mediates these regulatory effects on clock genes. The present study examined the molecular effects of dopamine D1 agonist on Per1, Per2, CLOCK, and Bmal1 expressions in the SCN and its effect on behavioral activities to determine the role of dopamine D1 receptor in regulation of these gene expressions and behavioral activities in adult male Wistar rats. To examine the molecular effects of dopamine D1 agonist day and night, we injected 20 mg/kg SKF38393 to the first group of rats at 6 a.m. and the second group at 6 p.m. We also injected saline to the third and fourth groups of rats at 6 a.m. and 6 p.m. as control groups. All rats were sacrificed 2 h following the injections. The real-time PCR technique was used to evaluate the clock gene expression. In addition, to examine the effects of dopamine D1 agonists on behavioral activities, we injected 20 mg/kg SKF38393 to SKF receiving group and saline to control group. The behavioral activities of the rats were monitored on the running wheel for 21 days, 1 week following the injections. SKF injections increased the Per2 and CLOCK expressions in the daytime and significantly decreased the Per1 and Bmal1 expressions. However, at night, SKF injections increased only Per2 expressions significantly and decreased the Per1, CLOCK, and Bmal1 genes expressions. Both saline receiving groups showed that all gene expressions were significantly higher except Per2 during nighttime. SKF injection increased the running wheel activity during nighttime significantly. Based on the obtained result, clock gene expression and behavioral activities in adult male Wistar rats may be altered or monitored by administration of exogenous dopamine.

Does Alzheimer's disease stem in the gastrointestinal system?

Over the last decades, our knowledge of the key pathogenic mechanisms of Alzheimer's disease (AD) has dramatically improved. Regarding the limitation of current therapeutic strategies for the treatment of multifactorial diseases, such as AD, to be translated into the clinic, there is a growing trend in research to identify risk factors associated with the onset and progression of AD. Here, we review the current literature with a focus on the relationship between gastrointestinal (GI)/liver diseases during the lifespan and the incidence of AD, and discuss the possible mechanisms underlying the link between the diseases. We also aim to review studies evaluating the possible link between the chronic use of the most common GI medications and the future risk of AD development.

Analgesic effects of cuminic alcohol (4-isopropylbenzyl alcohol), a monocyclic terpenoid, in animal models of nociceptive and neuropathic pain: Role of opioid receptors, L-arginine/NO/cGMP pathway, and inflammatory cytokines.

Cuminic alcohol (4-isopropylbenzyl alcohol; 4-IPBA) is a monocyclic terpenoid found in the analgesic medicinal plants Cuminum cyminum and Bunium persicum. The current study assessed the analgesic effects of 4-IPBA in different animal models of pain. Hot plate, formalin, and acetic acid tests were used to evaluate nociceptive pain in mice. The involvement of opioid receptors and the L-arginine/NO/cGMP/K+ channel pathway in 4-IPBA effects were investigated. Allodynia and hyperalgesia were assessed following peripheral neuropathy induced by chronic constriction of the sciatic nerve in rats. The spinal levels of inflammatory cytokines were measured using the ELISA method. The drugs and compounds were administered intraperitoneally. The results showed that 4-IPBA (200 and 400 mg/kg) significantly prolonged the hot plate latency. This effect was antagonized by naloxone (2 mg/kg). 4-IPBA (25-100 mg/kg) also significantly attenuated formalin- and acetic acid-induced nociceptive pain. L-arginine (200 mg/kg), sodium nitroprusside (0.25 mg/kg), and sildenafil (0.5 mg/kg) reversed while L-NAME (30 mg/kg) and methylene blue (20 mg/kg) potentiated the antinociceptive effects of 4-IPBA in the writhing test. Glibenclamide (10 mg/kg) and tetraethylammonium chloride (4 mg/kg) did not have any influence on the 4-IPBA effect. Furthermore, 4-IPBA (6.25-25 mg/kg) significantly relieved mechanical allodynia, cold allodynia, and hyperalgesia in rats. The concentrations of TNF-α and IL-1ß in the spinal cord of rats were decreased by 4-IPBA. No evidence of 4-IPBA-induced toxicity was found in behavioral or histopathological examinations. These results demonstrate that 4-IPBA attenuates nociceptive and neuropathic pain through the involvement of opioid receptors, the L-arginine/NO/cGMP pathway, and anti-inflammatory functions.

Attenuating effect of paroxetine on memory impairment following cerebral ischemia-reperfusion injury in rat: The involvement of BDNF and antioxidant capacity.

Memory impairments are frequently reported in patients suffering from brain ischemic diseases. Oxidative/nitrosative stress, synaptic plasticity, and brain-derived neurotrophic factor (BDNF) are involved in the physiopathology of brain ischemia-induced memory disorders. In the present study, the effect of paroxetine as an efficacious antidepressant medication with antioxidant properties was evaluated on passive avoidance memory deficit following cerebral ischemia in rats. Transient occlusion of common carotid arteries was applied to induce ischemia-reperfusion injury in male Wistar rats. Paroxetine (5, 10, 20 mg/kg) was administered intraperitoneally once daily before (for 3 days) or after (for 7 days) the induction of ischemia. A week after ischemia-reperfusion injury, passive avoidance memory, long-term potentiation (LTP), BDNF levels, total antioxidant capacity, the activity of antioxidant enzymes (including catalase, glutathione peroxidase, and superoxide dismutase), the concentration of malondialdehyde (MDA), and nitric oxide (NO) were investigated in the hippocampus. In the passive avoidance test, paroxetine significantly increased the step-through latency and decreased the time spent in the dark compartment. This affirmative function of paroxetine on the passive avoidance memory was accompanied by the improvement of hippocampal LTP and an obvious augmentation in the BDNF contents. Besides, paroxetine caused a significant rise in the total antioxidant capacity and antioxidant enzyme activity; while decreased the hippocampal levels of NO and MDA. It was ultimately attained that paroxetine attenuates cerebral ischemia-induced passive avoidance memory dysfunction in rats by the enhancement of hippocampal synaptic plasticity and BDNF content together with the suppression of oxidative/nitrosative stress.

Alpha-pinene exerts neuroprotective effects via anti-inflammatory and anti-apoptotic mechanisms in a rat model of focal cerebral ischemia-reperfusion.

BACKGROUND: Ischemic stroke is a severe neurological disorder that affected millions of people worldwide. Neuro-inflammation and apoptosis play an essential role in the pathogenesis of neuronal death during ischemic stroke. Alpha-pinene is a bicyclic terpenoid with anti-inflammatory and anti-apoptotic activities. Accordingly, the main purpose of this study was to assess the protective effect of α-pinene in ischemic stroke. MATERIALS AND METHODS: To induce ischemic stroke in male Wistar rats, the middle cerebral artery was occluded for 60 min followed by 24 h reperfusion. Alpha-pinene was injected intraperitoneally at the beginning of reperfusion. A day after reperfusion, the neurological deficits, volume of infarct area, and blood-brain barrier (BBB) permeability were evaluated. The mRNA expression of inflammatory cytokines as well as pro- and anti-apoptotic genes was assessed by using reverse transcription-polymerase chain reaction. The protein levels of inflammatory cytokines were also measured by ELISA method. RESULTS: The results showed that α-pinene (50 and 100 mg/kg) significantly improved sensorimotor function and decreased the volume of infarct area in the brain. The high permeability of BBB was also alleviated by α-pinene (50 and 100 mg/kg) in ischemic areas. Besides, α-pinene (100 mg/kg) attenuated neuro-inflammation through decreasing both the gene and protein expression of TNF-α and IL-1ß in the hippocampus, cortex, and striatum. Besides, α-pinene (100 mg/kg) suppressed apoptosis via downregulation of the pro-apoptotic Bax mRNA expression with a concomitant upregulation of anti-apoptotic Bcl-2 gene expression. CONCLUSIONS: Overall, it was concluded that α-pinene exerts neuroprotective effect during ischemic stroke through attenuating neuroinflammation and inhibition of apoptosis.

Antinociceptive and antineuropathic effects of cuminaldehyde, the major constituent of Cuminum cyminum seeds: Possible mechanisms of action.

ETHNOPHARMACOLOGICAL RELEVANCE: In Iranian traditional medicine, Cuminum cyminum is a unique medicinal herb for pain relief. Cuminaldehyde has been distinguished as the major constituent of C. cyminum seeds; even though, the analgesic effect of cuminaldehyde has not yet been examined. AIM OF THE STUDY: The nobility of this study was to assess cuminaldehyde effect on nociceptive and neuropathic pains; furthermore, evaluation of its possible mechanisms of action. MATERIALS AND METHODS: Hot plate, formalin, and acetic acid-induced writhing tests were used to evaluate nociception in mice. Naloxone (opioid receptors antagonist), L-arginine (nitric oxide (NO) precursor), L-NAME (NO synthase inhibitor), sodium nitroprusside (NO donor), methylene blue (guanylyl cyclase inhibitor), sildenafil (phosphodiesterase inhibitor), and glibenclamide (KATP channel blocker) were used to determine the implication of opioid receptors and L-arginine/NO/cGMP/KATP channel pathway. Allodynia and hyperalgesia were investigated in the CCI (chronic constriction injury) model of neuropathic pain in rats. The ELISA method was used to measure the inflammatory cytokines in serum samples of rats. The entire chemicals were intraperitoneally injected. RESULTS: Cuminaldehyde (100 and 200 mg/kg) significantly decreased the latency to nociceptive response in the hot plate test. The outcome of cuminaldehyde was completely antagonized by naloxone (2 mg/kg). Formalin- and acetic acid-induced nociception was significantly inhibited by cuminaldehyde (12.5-50 mg/kg). The antinociceptive effect of cuminaldehyde was reversed in writhing test by L-arginine (200 mg/kg), sodium nitroprusside (0.25 mg/kg), and sildenafil (0.5 mg/kg); however, L-NAME (30 mg/kg) and methylene blue (20 mg/kg) enhanced the effect of cuminaldehyde. Glibenclamide (10 mg/kg) did not alter the antinociceptive effects of cuminaldehyde. In the CCI-induced neuropathy, cuminaldehyde (25-100 mg/kg) significantly alleviated allodynia and hyperalgesia and decreased the serum levels of TNF-α and IL-1ß. CONCLUSION: It was attained magnificently that cuminaldehyde exerts antinociceptive and antineuropathic effects through the involvement of opioid receptors, L-arginine/NO/cGMP pathway, and anti-inflammatory function.

Attenuating effect of α-pinene on neurobehavioural deficit, oxidative damage and inflammatory response following focal ischaemic stroke in rat.

OBJECTIVES: Oxidative stress and inflammation have a critical role in the pathogenesis of ischaemic stroke. Alpha-pinene is a monoterpenoid molecule with anti-inflammatory and antioxidant properties. The nobility of the present study was to evaluate the neuroprotective effect of α-pinene in ischaemic stroke. METHODS: Ischaemic stroke was induced by transient middle cerebral artery occlusion followed by 24 h reperfusion in male Wistar rats. Alpha-pinene (25, 50 and 100 mg/kg, i.p.) was administered in the beginning of reperfusion. Then, the neurobehavioural function, infarct volume, brain oedema, antioxidant enzyme activity and the concentration of malondialdehyde (MDA), nitric oxide (NO) and interleukin-6 (IL-6) were evaluated by different methods in the brain. KEY FINDINGS: Alpha-pinene (50 and 100 mg/kg) elicited a significant decrease in the brain oedema and infarct size as well as an improvement in the neurobehavioural function. Besides, α-pinene (100 mg/kg) restored the function of superoxide dismutase, catalase and glutathione peroxidase and reduced the concentration of MDA, NO and IL-6 in the hippocampus, cortex and striatum. CONCLUSIONS: It was ultimately attainted that α-pinene exerts neuroprotective effect in ischaemic stroke in rat through the restoration of antioxidant enzymes activity, attenuation of lipid peroxidation and reduction of inflammation in the ischaemic brains.

In vitro and in vivo Assessment of Silver Nanoparticles Against Clostridium botulinum Type A Botulinum.

BACKGROUND: Clostridium botulinum causes botulism, a serious paralytic illness that results from the ingestion of a botulinum toxin. Because silver nanoparticle products exhibit strong antimicrobial activity, applications for silver nanoparticles in healthcare have expanded. Therefore, the objective of the current study was to assess a therapeutic strategy for the treatment of botulism toxicity using silver nanoparticles. METHODS: A preliminary test was conducted using doses that produce illness in laboratory animals to determine the absolute lethal dose (LD100) of botulinum toxin type A (BoNT/A) in mice. Next, the test animals were divided into six groups containing six mice each. Groups I, II and III were the negative control (botulinum toxin only), positive control-1 (nano-silver only) and positive control-2 (no treatment), respectively. The remaining groups were allocated to the toxin that was supplemented with three nano-silver treatments. RESULTS: The mortality rates of mice caused by BoNT/A significantly reduced in the treatment groups with different doses and injection intervals of nano-silver when compared to the negative control group. BoNT/A toxicity induced by intraperitoneal injection of the toxin of Clostridium botulinum causes rapid death while when coupled with nano-osilver results in delayed death in mice. CONCLUSION: These results, while open to future improvement, represent a preliminary step towards the satisfactory control of BoNT/A with the use of silver nanoparticles for human protection against this bioterrorism threat. Further study in this area can elucidate the underlying mechanism for detoxifying BoNT/A by silver nanoparticles.

Analgesic effect of α-terpineol on neuropathic pain induced by chronic constriction injury in rat sciatic nerve: Involvement of spinal microglial cells and inflammatory cytokines.

OBJECTIVES: Neuropathic pain is a prevalent and debilitating neurological disorder. Ample evidence indicates that microglial cells and inflammatory cytokines are involved in the pathogenesis of neuropathic pain. Alpha-terpineol is a monoterpenoid alcohol with inhibitory effect on inflammatory cytokines. The main purpose of this study was to evaluate the effect of α-terpineol on neuropathic pain in rats. MATERIALS AND METHODS: Chronic constriction injury (CCI) model was utilized to induce neuropathic pain in male Wistar rats. The rats were randomly divided into control, sham, α-terpineol, and gabapentin groups. Normal saline, α-terpineol (25, 50, and 100 mg/kg), and gabapentin (100 mg/kg) were administered intraperitoneally in the above-mentioned groups once daily for 14 days post-CCI. Behavioral tests, including Von Frey, acetone, and Hargreaves were used to assess mechanical allodynia, cold allodynia, and hyperalgesia in rats. Iba1 immunostaining and ELISA procedures were used to assess the activation of microglial cells and inflammatory cytokines level. RESULTS: The results showed that α-terpineol (50 and 100 mg/kg) significantly attenuated mechanical allodynia, cold allodynia, and hyperalgesia in the neuropathic rats. The analgesic effect of α-terpineol (100 mg/kg) was comparable with that of gabapentin as a standard antineuropathic pain drug. In addition, α-terpineol (25, 50 and 100 mg/kg) significantly decreased the number of Iba1-positive cells and diminished the concentration of IL-1ß and TNF-α in the spinal tissue. CONCLUSION: It was ultimately attained that α-terpineol attenuates neuropathic pain through the suppression of the microglial cells and reduction of inflammatory cytokine levels in the spinal cord of rats.

The Attenuating Effect of Curcumin on Morphine Dependence in Rats: The Involvement of Spinal Microglial Cells and Inflammatory Cytokines.

New evidence suggests an important role for spinal glial cells in the development of opioid dependence. Curcumin, a component of the Curcuma Longa, has shown to act as a suppressor of microglial cells. The main goal of this study was to explore the attenuating effects of curcumin on morphine dependence with a focus on spinal microglial cells and inflammatory cytokines. In order to induce morphine dependence in male Wistar rats, morphine was administered intraperitoneally (i.p.) once daily for 9 days in an increasing dose of 10, 20, and 40 mg/kg. Curcumin (2.5, 5, and 10 mg/kg, i.p.) was given from the days 10th to 18th. Naloxone-precipitated abstinence syndrome was used to assess the behavioral symptoms of morphine dependence. Immunofluorescence staining of Iba1 and ELISA test were used to measure spinal microglial activity and inflammatory cytokines levels, respectively. The results showed that curcumin (2.5, 5, and 10 mg/kg) significantly decreased jumping, leaning, and diarrhea in morphine-dependent rats. In addition, the spinal concentration of TNF-α and IL-6 was reduced by curcumin (2.5, 5, and 10 mg/kg) significantly. Moreover, curcumin showed a potent attenuating effect on the number of Iba1 positive cells in rats which were subjected to morphine dependence. The results of this study demonstrated that curcumin exerts a remarkable reducing effect on morphine dependence in rats. The findings showed that the therapeutic effect of curcumin on morphine dependence is mediated through the suppression of activated microglial cells and reduction of inflammatory cytokines levels in the spinal cord.

Role of L-arginine/NO/cGMP/KATP channel signaling pathway in the central and peripheral antinociceptive effect of thymoquinone in rats.

OBJECTIVES: Growing evidence demonstrates that L-arginine/NO/cGMP/KATP channel pathway has a modulatory role in pain perception. Previous studies have shown that thymoquinone exerts antinociceptive effects; however, the mechanisms underlying antinociception induced by thymoquinone have not been fully clarified. The aim of the present study was to evaluate the role of L-arginine/NO/cGMP/KATP channel pathway in the central and peripheral antinociceptive effect of thymoquinone in rats. MATERIALS AND METHODS: Rats were pretreated intraplantarly (IPL) or intracerebroventricularly (ICV) with L-arginine (the NO precursor), l-NAME (an NO synthase inhibitor), SNAP (an NO donor), methylene blue (a guanylyl cyclase inhibitor), glibenclamide (the blocker of KATP channel), and tetraethylammonium (TEA, a Kv channel blocker) before the injection of thymoquinone. RESULTS: Local ipsilateral (20 and 40 µg, IPL) but not contralateral and ICV (4 and 8 µg) administration of thymoquinone caused a dose-dependent and significant antinociception in both early and late phases of the formalin test. Pretreatment of rats with L-arginine (100 µg, IPL or ICV) and SNAP (200 µg, IPL or ICV) increased while l-NAME (100 µg, IPL or 1 µg, ICV) and methylene blue (400 µg, IPL or ICV) decreased the antinociceptive effects of thymoquinone in the formalin test. The administration of TEA (IPL or ICV) did not modify but glibenclamide (50 µg, IPL or ICV) significantly abolished the peripheral and central antinociceptive effects of thymoquinone in both phases of the formalin test. CONCLUSION: The results of the present study indicate that L-arginine/NO/cGMP/KATP channel pathway participates in the central and peripheral antinociceptive effect of thymoquinone.

Neuroprotective Effect of Paroxetine on Memory Deficit Induced by Cerebral Ischemia after Transient Bilateral Occlusion of Common Carotid Arteries in Rat.

Memory deficit is the most visible symptom of cerebral ischemia. The hippocampus is sensitive against cerebral ischemia. Oxidative stress and inflammation are involved in the pathological process after cerebral ischemic injury. Paroxetine has anti-oxidative and anti-inflammatory effects. In this study, the effect of paroxetine on memory deficit after cerebral ischemia was investigated. Cerebral ischemia/reperfusion (I/R) injury model was established using the bilateral occlusion of common carotid artery method. Paroxetine (10 mg/kg) was intraperitoneally injected into rats, 24 h before surgery or once a day for 7 days after surgery. Learning and memory were evaluated using the Morris water maze task, then the brain tissue was fixed and hippocampal CA1 pyramidal cells damage was analyzed using the Nissl staining method. In the ischemia group the escape latency time (ELT) and the swimming path length (SPL) were significantly increased and the time spent in target quadrant (TSTQ) was significantly decreased compared with the control group. The ELT and the SPL were significantly shortened and the TSTQ was significantly increased compared with the ischemia group after Pre- or post-ischemic administration of paroxetine. The percentage of viable pyramidal cells in the ischemia group was significantly decreased compared with the control group. The percentage of viable cells was significantly increased following pre-or post-ischemic administration of paroxetine compared with the ischemia group. Memory deficit due to I/R was improved and the percentage of viable cells in CA1 region was increased after administration of paroxetine. Therefore, paroxetine may have a neuroprotective effect against cerebral ischemia.

Role of l-arginine/SNAP/NO/cGMP/KATP channel signalling pathway in antinociceptive effect of α-terpineol in mice.

OBJECTIVES: The main purpose of this study was to assess the role of l-arginine/SNAP/NO/cGMP/KATP channel pathway in analgesic effects of α-terpineol in mice. METHODS: Male NMRI mice were pretreated intraperitoneally with NO precursor (l-arginine, 100 mg/kg), NO synthase inhibitor (l-NAME, 30 mg/kg), NO donor (SNAP, 1 mg/kg), guanylyl cyclase inhibitor (methylene blue, 20 mg/kg), PDE inhibitor (sildenafil, 0.5 mg/kg), KATP channel blocker (glibenclamide, 10 mg/kg) and naloxone (2 mg/kg) 20 min before the administration of α-terpineol. The formalin test was performed 20 min after the administration of α-terpineol, and nociceptive responses of mice were recorded during 30 min. KEY FINDINGS: A significant and dose-dependent antinociception was produced by α-terpineol (40 and 80 mg/kg) in both the phases of formalin test. The antinociceptive effect of α-terpineol was significantly potentiated by l-arginine in the second phase while significantly antagonized by l-NAME in both phases of formalin test. Also, SNAP and sildenafil non-significantly enhanced-while methylene blue significantly diminished-the antinociceptive effect of α-terpineol in both phases of formalin test. Glibenclamide significantly reversed the α-terpineol-induced antinociception, indicating the involvement of KATP channels in antinociceptive effect of α-terpineol. CONCLUSIONS: These results indicate that the antinociceptive effect of α-terpineol is mediated through l-arginine/SNAP/NO/cGMP/KATP channel pathway.

Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat.

Memory deficit is the most visible symptom of cerebral ischemia that is associated with loss of pyramidal cells in CA1 region of the hippocampus. Oxidative stress and inflammation may be involved in the pathogenesis of ischemia/reperfusion (I/R) damage. Minocycline, a semi-synthetic tetracycline derived antibiotic, has anti-inflammatory and antioxidant properties. We evaluated the neuroprotective effect of minocycline on memory deficit induced by cerebral I/R in rat. I/R was induced by occlusion of common carotid arteries for 20min. Minocycline (40mg/kg, i.p.) was administered once daily for 7days after I/R. Learning and memory were assessed using the Morris water maze test. Nissl staining was used to evaluate the viability of CA1 pyramidal cells. The effects of minocycline on the microglial activation was also investigated by Iba1 (Ionized calcium binding adapter molecule 1) immunostaining. The content of malondialdehyde (MDA) and pro-inflammatory cytokines (IL-1ß and TNF-α) in the hippocampus were measured by thiobarbituric acid reaction substances method and ELISA, respectively. Minocycline reduced the increase in escape latency time and in swimming path length induced by cerebral I/R. Furthermore, the ischemia-induced reduction in time spent in the target quadrant during the probe trial was increased by treatment with minocycline. Histopathological results indicated that minocycline prevented pyramidal cells death and microglial activation induced by I/R. Minocycline also reduced the levels of MDA and pro-inflammatory cytokines in the hippocampus in rats subjected to I/R. Minocycline has neuroprotective effects on memory deficit induced by cerebral I/R in rat, probably via its anti-inflammatory and antioxidant properties.