Adolescent swimming exercise following maternal valproic acid treatment improves cognition and reduces stress-related symptoms in offspring mice: Role of sex and brain cytokines.

Valproic acid (VPA) treatment during pregnancy is a risk factor for developing autism spectrum disorder, cognitive deficits, and stress-related disorders in children. No effective therapeutic strategies are currently approved to treat or manage core symptoms of autism. Active lifestyles and physical activity are closely associated with health and quality of life during childhood and adulthood. This study aimed to evaluate whether swimming exercise during adolescence can prevent the development of cognitive dysfunction and stress-related disorders in prenatally VPA-exposed mice offspring. Pregnant mice received VPA, afterwards, offspring were subjected to swimming exercise. We assessed neurobehavioral performances and inflammatory cytokines (interleukin-(IL)6, tumor-necrosis-factor-(TNF)α, interferon-(IFN)γ, and IL-17A) in the hippocampus and prefrontal cortex of offspring. Prenatal VPA treatment increased anxiety-and anhedonia-like behavior and decreased social behavior in male and female offspring. Prenatal VPA exposure also increased behavioral despair and reduced working and recognition memory in male offspring. Although prenatal VPA increased hippocampal IL-6 and IFN-γ, and prefrontal IFN-γ and IL-17 in males, it only increased hippocampal TNF-α and IFN-γ in female offspring. Adolescent exercise made VPA-treated male and female offspring resistant to anxiety-and anhedonia-like behavior in adulthood, whereas it only made VPA-exposed male offspring resistant to behavioral despair, social and cognitive deficits in adulthood. Exercise reduced hippocampal IL-6, TNF-α, IFN-γ, and IL-17, and prefrontal IFN-γ and IL-17 in VPA-treated male offspring, whereas it reduced hippocampal TNF-α and IFN-γ in VPA-treated female offspring. This study suggests that adolescent exercise may prevent the development of stress-related symptoms, cognitive deficits, and neuroinflammation in prenatally VPA-exposed offspring mice.

A Single Nucleotide Polymorphism in GAS5 lncRNA is Associated with Risk of Bladder Cancer in Iranian Population.

Down-regulation of the long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) has a pathogenic role in bladder cancer. Moreover, genomic variants of this lncRNA have been associated with risk of diverse cancers. In the present project, we genotyped two putative functional SNPs (rs2067079 and rs6790) in 122 bladder cancer patients and 150 age- and sex-matched healthy subjects. The rs2067079 was associated risk of bladder cancer in recessive inheritance model (TT vs.CC + CT: OR (95% Confidence interval (CI)) = 2.67 (1.27-5.62), adjusted P value = 0.02). The T G haplotype (rs2067079 and rs6790) increased the risk of bladder cancer in the assessed population (OR (95% CI) = 1.73 (1.18-2.56), adjusted P value = 0.02). Consequently, in the current project we introduced a novel risk locus for bladder cancer in Iranian population.

Glibenclamide mitigates cognitive impairment and hippocampal neuroinflammation in rats with type 2 diabetes and sporadic Alzheimer-like disease.

A growing body of evidence suggests that type 2 diabetes (T2D) is a risk factor for cognitive impairment and dementia. Both preclinical and clinical studies have provided evidence that brain insulin resistance is associated with cognitive decline in patients with T2D and sporadic Alzheimer disease (AD). Accordingly, antidiabetic medications have been suggested as potential drugs for the treatment of cognitive impairments in patients with sporadic AD. This study set out to determine whether glibenclamide (GBC), an antidiabetic agent, can ameliorate cognitive impairments in rats with T2D and sporadic AD. Both animal models were treated with GBC for 23 consecutive days. To assess working and spatial memory, animals were subjected to the Y-maze and Morris water-maze tests. We measured glucose and insulin levels in the blood, and inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 in the hippocampus of animals. Our findings indicated that T2D and sporadic AD impaired memory and elevated TNF-α and IL-6 in the hippocampus. We found increased glucose and insulin levels in the blood of T2D-induced rats but not of sporadic AD rats. In contrast, GBC treatment improved memory impairment, increased insulin, and reduced glucose and hippocampal inflammation in rats with T2D and sporadic AD. This study suggests that GBC could be considered as a potential treatment for cognitive deficits in patients with T2D and sporadic AD. Taken together, this study highlights the need for further studies in humans to test whether GBC treatment is associated with cognitive improvement in sporadic AD patients.

ATP-sensitive potassium-channel inhibitor glibenclamide attenuates HPA axis hyperactivity, depression- and anxiety-related symptoms in a rat model of Alzheimer's disease.

Affective disorders including depression and anxiety are among the most prevalent behavioral abnormalities in patients with Alzheimer's disease (AD), which affect the quality of life and progression of the disease. Dysregulation of the hypothalamic-pituitary-adrenal-(HPA) axis has been reported in affective disorders and AD. Recent studies revealed that current antidepressant drugs are not completely effective for treating anxiety- and depression-related disorders in people with dementia. ATP-sensitive-potassium-(KATP) channels are well-known to be involved in AD pathophysiology, HPA axis function and the pathogenesis of depression and anxiety-related behaviors. Thus, targeting of KATP channel may be a potential therapeutic strategy in AD. Hence, we investigated the effects of intracerebroventricular injection of Aß25-35 alone or in combination with glibenclamide, KATP channel inhibitor on depression- and anxiety-related behaviors as well as HPA axis response to stress in rats. To do this, non-Aß25-35- and Aß25-35-treated rats were orally treated with glibenclamide, then the behavioral consequences were assessed using sucrose preference, forced swim, light-dark box and plus maze tests. Stress-induced corticosterone levels following forced swim and plus maze tests were also evaluated as indicative of abnormal HPA-axis-function. Aß25-35 induced HPA axis hyperreactivity and increased depression- and anxiety-related symptoms in rats. Our results showed that blockade of KATP channels with glibenclamide decreased depression- and anxiety-related behaviors by normalizing HPA axis activity in Aß25-35-treated rats. This study provides additional evidence that Aß administration can induce depression- and anxiety-like symptoms in rodents, and suggests that KATP channel inhibitors may be a plausible therapeutic strategy for treating affective disorders in AD patients.

Role of orexin-2 and CB1 receptors within the periaqueductal gray matter in lateral hypothalamic-induced antinociception in rats.

Orexin plays an important role in pain modulation. Orexin-1 and orexin-2 receptors (Ox1r and Ox2r) are found at high density in the ventrolateral periaqueductal gray matter (vlPAG). Our previous study showed that chemical stimulation of the lateral hypothalamus with carbachol induces antinociception in the tail-flick test, a model of acute pain, and Ox1r-mediated antinociception in the vlPAG is modulated by the activity of vlPAG CB1 receptors. In the current study, TCS OX2 29, an Ox2r antagonist (5, 15, 50, 150, and 500 nmol/l), was microinjected into the vlPAG 5 min before the administration of carbachol (125 nmol/l). TCS OX2 29 dose dependently reduced carbachol-induced antinociception. In a second set of experiments, animals were treated with carbachol 5 min after intra-vlPAG administration of 15 nmol/l TCS OX2 29 and 1 nmol/l AM251 (a selective CB1 receptor antagonist), or 150 nmol/l TCS OX2 29 and 10 nmol/l AM251. The findings showed that the antinociceptive effect of orexin is partially mediated by activation of vlPAG Ox2 receptors. Furthermore, the administration of ineffective doses of Ox2 and CB1 receptor antagonists reduced the lateral hypothalamus-induced antinociception. It seems that Ox2 and CB1 receptors act through different pathways and Ox2r-mediated antinociception is not dependent on CB1 receptor activity.

Orexin receptor type-1 antagonist SB-334867 decreases morphine-induced antinociceptive effect in formalin test.

Orexin-A and orexin-B are two neuropeptides selectively synthesized in the lateral hypothalamus (LH), a region involved in morphine induced analgesia and pain modulation. Furthermore, orexin-A has been reported to produce an analgesic effect in pain models, which was blocked by orexin-1 receptor antagonist SB-334867, but not naloxone. We studied the effects of intracerebroventricular (ICV) injection of SB-334867, a selective orexin receptor type-1 antagonist, on morphine-induced antinociceptive effect in formalin test in rats. Morphine injection at a dose of 1.5mg/kg caused a significant decrease in the formalin-induced nociceptive behaviors in phase 1, interphase, and phase 2A, whereas at doses of 3, 6, and 10mg/kg, a significant reduction in the formalin-induced nociceptive behaviors was observed in all phases. The ICV injection of SB-334867 alone had no effect on the formalin-induced nociceptive behaviors. Pre-treatment with SB-334867 at a dose of 0.5 nmol significantly attenuated the analgesia induced by morphine (at dose 1.5mg/kg of morphine; interphase and phase 2B and at dose 3mg/kg of morphine just phase 2B of formalin test). Also, pre-treatment with SB-334867 at a dose of 5 nmol considerably attenuated the morphine-induced analgesia (at dose 1.5mg/kg of morphine; phase 1, interphase, and phase 2, at dose 3 and 6 mg/kg of morphine just phase 2 of formalin test). Pre-treatment with SB-334867 at a dose of 50 nmol remarkably attenuated the morphine-induced analgesia (at dose 1.5 and 3mg/kg of morphine; in phase 1, interphase, and phase 2 and also at dose 6 mg/kg of morphine; phase 1 and phase 2B of formalin test). These data suggest that the antinociceptive effects of morphine in formalin test might be associated with orexin receptor type-1. Our findings reveal a new role for the lateral hypothalamus orexin neurons in the morphine-induced analgesia.

Intrahippocampal administration of D2 but not D1 dopamine receptor antagonist suppresses the expression of conditioned place preference induced by morphine in the ventral tegmental area.

The ventral tegmental area (VTA) as a major source of dopamine neurons projecting to cortical and limbic regions has a crucial role in reward and addiction. The current study assessed the role of D1 and D2 receptors within the dorsal hippocampus (CA1) in the expression of conditioned place preference (CPP) by intra-VTA morphine in the rats. In the present study, 160 adult male albino Wistar rats weighing 220-290g were bilaterally implanted by two cannulae into the CA1 and VTA. The CPP paradigm was done and animal displacement, conditioning score and locomotor activity were recorded. For blocking the dopamine D1/D2 receptors in the dorsal hippocampus, SCH23390 (0.02, 0.05, 0.2 and 0.5µg per side) or sulpiride (0.25, 0.75, 1.5 and 3µg per side) were microinjected into the CA1, just 5min before the CPP test on the post-conditioning day. All animals received intra-VTA morphine (1µg per side) during 3-days conditioning phase. Our results showed that sulpiride (1.5 and 3µg) but not SCH23390 in the dorsal hippocampus significantly decreased the expression of CPP induced by intra-VTA morphine (p<0.001). Intra-CA1 administration of these antagonists alone, in all doses, could not induce CPP. We suggest that D2 receptors in the CA1 region of hippocampus have a key role in the expression of CPP induced by morphine at the level of the VTA and there is a relationship between dopaminergic D2 receptors and opioidergic systems in these areas in reward circuit.

Intra-paragigantocellularis lateralis injection of orexin-A has an antinociceptive effect on hot plate and formalin tests in rat.

In the present study, the effect of orexin-A (ORXA) microinjection into the paragigantocellularis lateralis (LPGI) on nociceptive behaviors, using hot-plate and formalin tests as thermal and chemical models of pain in rat, was examined. Also, we determined whether the pretreatment with SB-334867, a selective OX1-receptor antagonist, would prevent the antinociceptive effect of orexin-A. ORXA (0.1-100 nM/0.5 µL) microinjected into the LPGi nucleus, dose-dependently decreased the formalin induced nociceptive behaviors and also produced a dose-dependent antinociceptive effect in the hot-plate test. Pretreatment with a selective orexin receptor 1 (OX1R) antagonist, SB-334867, also inhibited the effect of ORXA on formalin induced nociceptive behaviors while the SB-334867 (100 µM) alone had no effect on formalin test. These data demonstrated that the ORXA-induced antinociception in formalin test is mainly mediated through the OX1R in LPGi which might play a potential role in processing the pain information associated with descending pain modulation.

Intracerebral injection of low amounts of norharman induces moderate Parkinsonism-like behavioral symptoms in rat.

ß-Carbolines (BCs) are considered to be endogenous toxins and have been proposed as possible causative candidates inducing Parkinson's disease (PD). However, there is controversy about the effect and also effective dose of these compounds in the etiology of PD. This study was designed to further examine the effect of norharman (NH), a BC which in mammalian brain occurs at high levels in the substantia nigra, on the development of Parkinsonism-like behaviors in rats. A small amount (4µl) of NH solution at 2 or 200ng/ml was unilaterally injected into either striatum or substantia nigra (SN) by stereotaxic surgery. The development of Parkinsonism was assessed by three conventional behavioral tests, compared to the effects of unilateral 6-hydroxydopamine (6-OHDA) - induced lesions in the nigrostriatal pathway. An apomorphine-induced rotational test revealed no Parkinsonism-like behavior in the NH treated groups. However, rats that received the high concentration of NH into their SN showed significant biased swings in the elevated body swing test. In a rotarod test, NH treated groups showed relatively weak motor performance and their learning patterns were close to that of the 6-OHDA treated rats. Considering that the rotational test is only valid in animals with severe Parkinsonism, but time spent on the rotating rod correlates inversely with severity of Parkinsonism, our results indicate that a single exposure to low amounts of NH is effective in producing moderate Parkinsonism-like behavioral symptoms, possibly through a neurotoxic effect of this agent on the SN dopaminergic neurons.

Transient inactivation of the nucleus accumbens reduces both the expression and acquisition of morphine-induced conditioned place preference in rats.

In the present study, the effects of transient inhibition of the shell and core parts of the nucleus accumbens by lidocaine on the expression and acquisition of morphine-induced conditioned place preference in male Wistar rats were investigated. In addition, the number of bouts of sniffing, rearing, and compartment crossing was scored. Lidocaine hydrochloride was injected into different parts of the nucleus accumbens 5 min before each morphine session for the transient inhibition of particular anatomical regions. Subcutaneous (s.c.) injection of morphine (2.5 and 5mg/kg) induced place preference. Transient inhibition of the left and/or right side of the shell part of nucleus accumbens reduced morphine place conditioning. However, when both sides of the nucleus were inhibited, inhibition was weaker when compared to the results when only one side was inhibited. Also, the number of compartment crossings in these animals reduced significantly. Nevertheless, the number of rearing occurrences was reduced only when both sides of the shell part of the nucleus accumbens were inhibited. In contrast, the number of sniffing bouts increased in all three groups. The results for the core part of the nucleus accumbens also indicated that place preference was inhibited after transient inhibition of the left, right, and both sides. However, although the number of total compartment crossings was reduced in all experimental groups, the reduction was not statistically significant. The data obtained was similar to the number of rearings, yet the number of sniffing bouts increased in the experimental groups compared to the control. In conclusion, these results confirmed the involvement of the left and right sides and core and shell parts of the nucleus accumbens in morphine place conditioning.

Role of D1/D2 dopamine receptors in the CA1 region of the rat hippocampus in the rewarding effects of morphine administered into the ventral tegmental area.

Considerable evidences show that the VTA, as a major source of dopamine neurons projecting to cortical and limbic regions, has a major role in cognitive and motivating aspects of addiction. The current study assessed the ability of the selective D1 receptor antagonist SCH 23390 and D2 receptor antagonist sulpiride administrated into the CA1 region of hippocampus (dorsal hippocampus) to alter the rewarding effects of intra-VTA administration of morphine using the conditioned place preference (CPP). After bilaterally implantation of cannulae into the CA1 and/or VTA in adult male Wistar rats weighing 210-310 g, dose-response effects of different doses of intra-VTA morphine (0.03, 0.1, 0.3, 1 and 3 µg/side) on CPP paradigm were evaluated and animal displacement, conditioning score and locomotor activity were recorded by Ethovision software. In the next experiments, SCH 23390 (0.02, 0.05, 0.2 and 0.5 µg/side) or sulpiride (0.25, 0.75, 1.5 and 3 µg/side) were injected into the CA1, 5 min after intra-VTA injection of morphine during 3 days conditioning phase. Our results showed that intra-VTA morphine dose-dependently induces CPP in rats. Moreover, the blocking D1 and D2 receptors in the dorsal hippocampus decreased intra-VTA morphine-induced CPP significantly (P<0.01). Intra-CA1 administration of these antagonists alone, in all doses, could not induce CPP. We suggest that D1 and D2 receptors in the CA1 region of hippocampus have a key role in the development of CPP induced by morphine at the level of the VTA. It seems that there is an interaction between dopaminergic and opioidergic systems in these areas in reward circuit.