Adenosine receptor mediates nicotine-induced antinociception in formalin test

In this study, the effect of adenosine receptor agents on nicotine induced antinociception, in formalin test, has been investigated. Intraperitoneal (i.p.) administration of different doses of nicotine (0.1, 1, 10 and 100 μg kg -1) induced a dose-dependent antinociception in mice, in the both first and second phases of the test. Adenosine receptor antagonist, theophylline (5, 10, 20 and 80 mg kg-1, i.p.) also induced antinociception in the both phases, while a dose of the drug (40 mg kg-1, i.p.) did not induce any response. Theophylline reduced antinociception induced by nicotine in both phases of formalin test. The A2 receptor agonist, 5�-N-ethylcarboxamide adenosine (NECA; 1 and 5 μg kg-1, i.p.) also produced antinociception, which was reversed with different doses of theophylline (5, 10, 20 and 40 mg kg-1, i.p.). But administration of the adenosine receptor agonist, NECA did not potentiate the response of nicotine. It is concluded that adenosine system may be involved in modulation of antinociception induced by nicotine. © 2004 Elsevier Ltd. All rights reserved

The effects of lithium chloride and cathodal/anodal transcranial direct current stimulation on conditional fear memory changes and the level of p-mTOR/mTOR in PFC of male NMRI mice

Lithium chloride clinically used to treat mental diseases but it has some side effects like cognitive impairment, memory deficit. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is able to change neural activity and gene transcription in the brain. The aim of the study is to provide a conceptual theoretical framework based on behavioral and molecular effects of tDCS on memory changes induced by lithium in male mice. we applied Anodal-tDCS and Cathodal-tDCS over the left PFC for 3 consecutive days tDCS for 20 min with 2 mA after injection of different doses of lithium/saline.Trained in fear condition and finally the day after that tested their memory persistency factors (freezing-latency) and other behavior such as grooming and rearing percentage time in the fear conditioning. P-mTOR/mTOR was analyzed using western blotting. The results obtained from the preliminary analysis of behavioral fear memory showed that lithium had destructive effect in higher doses and decreased freezing percentage time. However, both cathodal and anodal tDCS significantly improved memory and increased P-mTOR/mTOR level in the PFC. The results of this study indicate that cathodal and anodal tDCS upon the left prefrontal increased memory and reduced lithium side effects on memory consolidation and altered expression of plasticity-associated genes in the prefrontal cortex. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Influence of intracerebral administration of NO agents in dorsal hippocampus (CA1) on cannabinoid state-dependent memory in the step-down passive avoidance test

In the present study, the effects of nitric oxide agents on WIN55, 212-2 induced state-dependent memory of passive avoidance task were examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Post-training intra-CA1 administration of CB1 and CB2 receptor agonists, WIN55, 212-2 (0.25, 0.5 and 1μg/mouse), dose-dependently decreased memory retrieval. The memory impairment induced by post-training administration of WIN55, 212-2 (1μg/mouse) was restored by pre-test administration of the same dose of the drug (1μsg/mouse, intra-CA1), showing the WIN55, 212-2 state-dependent memory. Single intra-CA1 administration of l-arginine (0.3, 1 and 3μg/mouse) or L-NAME (0.3, 1 and 3μg/mouse), 5. min pre-test could not alter memory retrieval. On the other hand, in the animals in which retrieval was impaired due to post-training administration of WIN55, 212-2 (1μg/mouse), pre-test intra-CA1 administration of l-arginine (1 and 3μg/mouse), but not L-NAME (0.3, 1 and 3μg/mouse) 24. h after training restored memory retrieval. Also, in the animals which received both post-training (1μg/mouse) and pre-test injections of WIN55, 212-2 (1μg/mouse), the injection of L-NAME (3μg/mouse, intra-CA1), 2. min before pre-test administration decreased retrieval. Furthermore, in the animals under the influence of post-training administration of WIN55, 212-2 (1μg/mouse), pre-test co-administration of non-effective doses of WIN55, 212-2 (0.25μg/mouse) and l-arginine (0.3 and 1μg/mouse), increased the restoration of memory by pre-test WIN55, 212-2. These findings may demonstrate the involvement of NO in state-dependent memory induced by intra-CA1 administration of WIN55, 212-2. © 2010 Elsevier Inc

Combination therapy with dipeptidyl peptidase-4 and P2X7 purinoceptor inhibitors gives rise to antiepileptic effects in rats

Objective(s): Although the available therapeutic agents alleviate the symptoms in patients with temporal lobe epilepsy (TLE), these antiepileptic drugs do not provide adequate control of seizures in 30�40 of patients. This study was conducted to evaluate anti-epileptic effects of simultaneous inhibition of dipeptidyl peptidase-4 and P2 � 7 purinoceptors in Kainate treated rats. Materials and Methods: Brilliant Blue G)BBG(, linagliptin)lin(and lin + BBG were administrated 30 min prior to induction of the intrahippocampal kainate model of epilepsy in male Wistar rats. In the case of valproic acid group, the animals intraperitoneally received valproic acid for 7 consecutive days prior to induction of the model. We carried out histological evaluations, monitoring of behavior, recording of intracranial electroencepholography (IEEG), and determination of astrogliosis and DNA fragmentation using ELISA methods. Results: Our results showed that BBG and lin combination therapy had better effects on decrease in astrogliosis, DNA fragmentation and cognitive disturbances than ones whereas its effects on neuronal survival and seizure severity was similar to only BBG or lin. Likewise, the effects of lin + BBG on decrease in DNA fragmentation and cognitive disturbances were better than valproic acid group. Conclusion: Our findings suggest that simultaneous inhibition of dipeptidyl peptidase-4 and P2 � 7 purinoceptors might more efficiently provide protection against progression of the kainate-induced TLE in rats. © 2020 Elsevier B.V

The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson's disease: Involvement of PKA/CaMKII/CREB signaling

Parkinson's disease (PD) is a prevalent movement disorder in the elderly. PD is hallmarked with progressive deterioration of mesencephalic dopaminergic neurons and development of debilitating motor and non-motor clinical symptoms. Klotho protein is the product of an aging-suppressor gene that its overexpression could protect neurons against oxidative injury. This study was undertaken to explore whether exogenous klotho could alleviate injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with klotho at a dose of 10 μg/rat. Results showed that klotho mitigates apomorphine-induced rotational behavior and reduces the latency to initiate and the total time in the narrow beam test. In addition, beneficial effect of klotho was attenuated following i.c.v. microinjection of protein kinase A (PKA) inhibitor H-89 and Ca(2 +)/calmodulin-dependent protein kinase II (CamKII) inhibitor KN-62. Additionally, klotho significantly lowered striatal levels of malondialdehyde (MDA), reactive oxygen species (ROS), glial fibrillary acid protein (GFAP), α synuclein, phospho-cAMP-response element binding protein (pCREB), and DNA fragmentation. Furthermore, klotho was capable to prevent degeneration of tyrosine hydroxylase (TH)-positive neurons within substantia nigra pars compacta (SNC). Collectively, these findings denote neuroprotective potential of exogenous klotho in 6-OHDA rat model of PD through alleviation of astrogliosis, apoptosis, and oxidative stress. It was also obtained that part of its protective effect is dependent on PKA/CaMKII/CREB signaling cascade. © 2017 Elsevier Inc

Visfatin reduces hippocampal CA1 cells death and improves learning and memory deficits after transient global ischemia/reperfusion

Visfatin is a novel adipocytokine with insulin-mimetic effect which plays a role in glucose-lowering effect of insulin and improves insulin sensitivity. It has been linked to a variety of cellular processes and its plays important roles in cell apoptosis and survival. Moreover, cerebral ischemia causes loss of hippocampus pyramidal cells, therefore, in this study; we investigated the neuroprotective effect of visfatin after global cerebral ischemia in male rats. Both common carotid arteries were occluded for 20 minutes followed by 4 days of reperfusion. Animals were treated with either the Visfatin (intracerebro-ventricular; 100 ng) or saline vehicle (2 μl) at the time of reperfusion. Behavioral examination, apoptosis and necrosis assessment were performed 4 days after ischemia. Visfatin significantly reduced Caspase-3 activation (P < 0.001), TUNEL positive cells (P < 0.05) and necrotic cell death in the CA1 region of the hippocampus (P < 0.001). Moreover, treatment with visfatin significantly improved memory deficits of cerebral ischemia-reperfusion rats (P < 0.05). The results suggest that visfatin via its antiapoptotic properties has significant neuroprotective effects on cerebral ischemia reperfusion injury in rats. © 2014 Elsevier Ltd

The effects simultaneous inhibition of dipeptidyl peptidase-4 and P2X7 purinoceptors in an in vivo Parkinson�s disease model

Loss of dopaminergic neurons following Parkinson�s disease (PD) diminishes quality of life in patients. The present study was carried out to investigate the protective effects of simultaneous inhibition of dipeptidyl peptidase-4 (DPP-4) and P2X7 purinoceptors in a PD model and explore possible mechanisms. The 6-hydroxydopamine (6-OHDA) was used as a tool to establish PD model in male Wister rats. The expressions of SIRT1, SIRT3, mTOR, PGC-1α, PTEN, P53 and DNA fragmentation were evaluated by ELISA assay. Behavioral impairments were determined using apomorphine-induced rotational and narrow beam tests. Dopamine synthesis and TH-positive neurons were detected by tyrosine hydroxylase (TH) immunohistochemistry. Neuronal density was determined by Nissl staining. OHDA-lesioned rats exhibited behavioral impairments that reversed by BBG, lin and lin + BBG. We found significant reduced levels of SIRT1, SIRT3, PGC-1α and mTOR in both mid brain and striatum from OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Likewise, significant increased levels of PTEN and P53 were found in both mid brain and striatum from OHDA-lesioned rats that was reversed by BBG, lin and lin + BBG. TH-positive neurons and neuronal density were markedly reduced OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Collectively, our results showed protective effects of simultaneous inhibition of DPP-4 and P2X7 purinoceptors in a rat model of PD can be linked to targeting SIRT1/SIRT3, PTEN-mTOR pathways. Moreover, our findings demonstrated that simultaneous inhibition of DPP-4 and P2X7 purinoceptors might have stronger effect on mitochondrial biogenesis compared to only one. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson's disease: Involvement of PKA/CaMKII/CREB signaling

Parkinson's disease (PD) is a prevalent movement disorder in the elderly. PD is hallmarked with progressive deterioration of mesencephalic dopaminergic neurons and development of debilitating motor and non-motor clinical symptoms. Klotho protein is the product of an aging-suppressor gene that its overexpression could protect neurons against oxidative injury. This study was undertaken to explore whether exogenous klotho could alleviate injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with klotho at a dose of 10 μg/rat. Results showed that klotho mitigates apomorphine-induced rotational behavior and reduces the latency to initiate and the total time in the narrow beam test. In addition, beneficial effect of klotho was attenuated following i.c.v. microinjection of protein kinase A (PKA) inhibitor H-89 and Ca(2 +)/calmodulin-dependent protein kinase II (CamKII) inhibitor KN-62. Additionally, klotho significantly lowered striatal levels of malondialdehyde (MDA), reactive oxygen species (ROS), glial fibrillary acid protein (GFAP), α synuclein, phospho-cAMP-response element binding protein (pCREB), and DNA fragmentation. Furthermore, klotho was capable to prevent degeneration of tyrosine hydroxylase (TH)-positive neurons within substantia nigra pars compacta (SNC). Collectively, these findings denote neuroprotective potential of exogenous klotho in 6-OHDA rat model of PD through alleviation of astrogliosis, apoptosis, and oxidative stress. It was also obtained that part of its protective effect is dependent on PKA/CaMKII/CREB signaling cascade. © 2017 Elsevier Inc

Research paper: Ibuprofen protection against restrained chronic stress-induced depression in male rats

Introduction: Stress predisposes organisms to depression and cognitive impairments, and seems to interact with metabolic homeostasis. The inflammatory response and the upregulation of proinflammatory cytokines are some of the consequences related to chronic stress. In this study, we investigated the preventive effect of chronic administration of ibuprofen, as an inhibitor of cyclooxygenases, on the cognitive and behavioral alterations and the weight gain reduction induced by simultaneous chronic restraint stress in rats. Materials and Methods: Male Wistar rats were subjected to chronic restraint stress and injected daily with the variable doses of ibuprofen or vehicle, for 21 consecutive days. Then, all animals were tested with the forced swim test and passive avoidance conditioning. Also, the weight of the animals was recorded before and after the interventions. Ultimately, plasma interleukin 6 (IL-6) levels were measured. Results: Chronic stress increased depressive-like behaviors, impaired learning, and disrupted the normal weight gain. However, the animals that received the highest dose of ibuprofen showed less depressive-like behaviors, a better avoidance memory, and a higher weight gain. However, the level of plasma IL-6 did not differ significantly between the study groups. Conclusion: The administration of ibuprofen prevents the cognitive and behavioral consequences of chronic stress. During the recovery, the plasma levels of IL-6 were not elevated by stress, and the IL-6 levels did not predict the behavioral performance of the stressed animals. The exact mechanisms of the protective effects of ibuprofen against chronic stress need to be further investigated. © 2020 Iran University of Medical Sciences. All rights reserved