Synergistic effects of citicoline and silymarin nanomicelles in restraint stress-exposed mice.

This study evaluated the effects of citicoline and silymarin nanomicelles (SMnm) in repeated restraint stress (RRS). METHOD: Mice were exposed to RRS for four consecutive days, 2 hrs. daily. On day 5 of the study, SMnm (25 and 50 mg/kg, i.p.) and citicoline (25 and 75 mg/kg), and a combination of them (25 mg/kg, i.p.) were initiated. On day 18, anxiety-like behavior, behavioral despair, and exploratory behavior were evaluated. The prefrontal cortex (PFC) and the hippocampus were dissected measuring brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and tumor necrosis factor-alpha (TNF-α) through Western Blot and ELISA, respectively. RESULTS: In RR-exposed mice, anxiety-like behavior in the elevated plus maze (EPM) was enhanced by reductions in open arm time (OAT%) P < 0.001, and open arm entry (OAE%) P < 0.001. In the forced swimming test (FST), the immobility increased P < 0.001 while the swimming and climbing reduced P < 0.001. In the open field test (OFT), general motor activity was raised P < 0.05. Further, body weights reduced P < 0.001, and tissue BDNF and pCREB expressions decreased P < 0.001 while TNF-α increased P < 0.001. Conversely, SMnm, citicoline and their combination could reduce anxiety-like behavior P < 0.001. The combination group reduced the depressive-like behaviors P < 0.001. Moreover, body weights were restored P < 0.001. Besides, BDNF and pCREB expressions increased while TNF-α reduced, P < 0.001. CONCLUSION: The combination synergistically improved emotion-like behaviors, alleviating the inflammation and upregulating the hippocampal BDNF-mediated CREB signaling pathway.

The effect of nicotine on antidepressant and anxiolytic responses induced by citalopram and citicoline in mice.

The effect of nicotine on both anxiety and depression has been broadly studied. Moreover, citalopram and citicoline play a role in the modulation of anxiety and depression. This study was designed to examine the effects of nicotine on the antidepressant and anxiolytic responses induced by citalopram and citicoline in mice. Anxiety­ and depression­related behaviors were assessed with the elevated plus maze and forced swim test, respectively. The results showed that subcutaneous administration of nicotine decreased open­arm time (OAT) and open­arm entries (OAE) but increased immobility time, suggesting anxiogenic­like and depressive­like effects. Intraperitoneal administration of citalopram increased OAT but decreased immobility time, indicating that citalopram induced anxiolytic­like and antidepressant­like responses. Additionally, an injection of citicoline increased OAE but decreased immobility time, revealing anxiolytic­like and antidepressant­like effects. Interestingly, the subthreshold dose of nicotine potentiated the citalopram and citicoline effects on OAT and immobility time, which revealed anxiolytic­like and antidepressant­like behaviors. Locomotor activity was not significantly changed by any doses of the drugs. In conclusion, these findings suggest that interactions between nicotine and citalopram or citicoline occur upon induction of anxiolytic and antidepressant responses in mice.

The Interaction Effect of Sleep Deprivation and Treadmill Exercise in Various Durations on Spatial Memory with Respect to the Oxidative Status of Rats.

Sleep deprivation (SD) has deleterious effects on cognitive functions including learning and memory. However, some studies have shown that SD can improve cognitive functions. Interestingly, treadmill exercise has both impairment and improvement effects on memory function. In this study, we aimed to investigate the effect of SD for 4 (short-term) and 24 (long-term) hours, and two protocols of treadmill exercise (mild short-term and moderate long-term) on spatial memory performance, and oxidative and antioxidant markers in the serum of rats. Morris Water Maze apparatus was used to assess spatial memory performance. Also, SD was done using gentle handling method. In addition, the serum level of catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) was measured. The results showed that 24 h SD (but not 4 h) had negative effect on spatial memory performance, decreased SOD, CAT, and GSH-Px level, and increased MDA level. Long-term moderate (but not short-term mild) treadmill exercise had also negative effect on spatial memory performance, decreased SOD, CAT, and GSH-Px level, and increased MDA level. Interestingly, both protocols of treadmill exercise reversed spatial memory impairment and oxidative stress induced by 24 h SD. In conclusion, it seems that SD and treadmill exercise interact with each other, and moderate long-term exercise can reverse the negative effects of long-term SD on memory and oxidative status; although, it disrupted memory function and increased oxidative stress by itself.

Intricate role of sleep deprivation in modulating depression: focusing on BDNF, VEGF, serotonin, cortisol, and TNF-α.

In this review article, we aimed to discuss intricate roles of SD in modulating depression in preclinical and clinical studies. Decades of research have shown the inconsistent effects of SD on depression, focusing on SD duration. However, inconsistent role of SD seems to be more complicated, and SD duration cannot be the only one factor. Regarding this issue, we chose some important factors involved in the effects of SD on cognitive functions and mood including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), serotonin, cortisol, and tumor necrosis factor-alpha (TNF-α). It was concluded that SD has a wide-range of inconsistent effects on BDNF, VEGF, serotonin, and cortisol levels. It was noted that BDNF diurnal rhythm is significantly involved in the modulatory role of SD in depression. Furthermore, the important role of VEGF in blood-brain barrier permeability which is involved in modulating depression was discussed. It was also noted that there is a negative correlation between cortisol and BDNF that modulates depression. Eventually, it was concluded that TNF-α regulates sleep/wake cycle and is involved in the vulnerability to cognitive and behavioral impairments following SD. TNF-α also increases the permeability of the blood-brain barrier which is accompanied by depressive behavior. In sum, it was suggested that future studies should focus on these mechanisms/factors to better investigate the reasons behind intricate roles of SD in modulating depression.

The role of sleep deprivation in streptozotocin-induced Alzheimer's disease-like sporadic dementia in rats with respect to the serum level of oxidative and inflammatory markers.

Numerous studies have shown the deleterious effects of sleep deprivation (SD) on memory. However, SD in various durations may induce different effects. Studies have reported that short-term or acute SD can improve cognitive functions. In addition, streptozotocin (STZ) significantly impairs learning and memory, and induces inflammation and oxidative stress. In this study, we aimed to investigate the effect of two types of SD (short term: 6 h; long term: 24 h) on STZ-induced spatial memory impairment in rats, with respect to the serum level of catalase (CAT), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß). Morris water maze apparatus was used to assess spatial memory performance and STZ was injected i.c.v., twice, and at the dose of 3 mg/kg, at an interval of 48 h. The results showed that only 24 h SD impaired spatial learning and memory in rats. In addition, 24 h SD attenuated anti-oxidant activity and increased the level of pro-inflammatory markers in the serum. STZ impaired spatial learning and memory, and attenuated anti-oxidant activity and increased the level of pro-inflammatory markers in the serum of rats. Furthermore, 6 h SD slightly and partially improved spatial memory and significantly improved anti-oxidant activity in rats, with no effect on STZ-induced inflammation. We suggest that STZ has more important mechanisms that are involved in its memory impairment effect, and maybe, STZ-induced inflammation has a more important role. We also suggest more detailed studies to investigate the potential therapeutic effect of SD (in different durations) on memory function, oxidative stress, and inflammation.

Isobolographic analysis of the antidepressant interaction in two-drug combinations of citalopram, bupropion, and scopolamine in mice.

Depression and anxiety are psychiatric diseases that commonly occur together, and the patient burden and complexity increase when both are present. Comorbid anxiety and depression are often more resistant to common drug treatments such as antidepressants. Combination therapy is a suggested approach in treating these patients, where a decline of doses could reduce undesirable outcomes and still achieve optimal effects. We, therefore, conducted a preclinical study to assess the effect of two-drug combinations of citalopram, bupropion, and scopolamine on anxiety- and antidepressive-like behaviors in male NMRI mice and aimed to determine the nature of the interaction between components. Anxiety- or antidepressive-like activity of mice was assessed by the hole-board or forced swim test (FST), respectively. Our results revealed that citalopram (0.01-0.25 mg/kg; i.p.), bupropion (1-9 mg/kg; i.p.), or scopolamine (0.01-0.1 mg/kg; i.p.) diminished immobility time in the FST, suggesting an antidepressive-like effect. Citalopram decreased dead-dip counts in the hole-board, indicating an anxiogenic-like activity. All two-drug combinations, at inactive doses, exerted an antidepressive-like behavior. Only bupropion/scopolamine combination increased head-dip counts compared to the bupropion/saline group. Isobolographic analysis revealed an antidepressive synergy effect between citalopram plus bupropion, and an antidepressive additive impact between scopolamine plus citalopram or bupropion. It should be noted that the higher dose of each drug alone declined locomotor activity, while two-drug combinations did not affect this parameter. These results suggest a stronger antidepressive effect for citalopram/bupropion combination than other two-drug combinations.

Complicated Role of Exercise in Modulating Memory: A Discussion of the Mechanisms Involved.

Evidence has shown the beneficial effects of exercise on learning and memory. However, many studies have reported controversial results, indicating that exercise can impair learning and memory. In this article, we aimed to review basic studies reporting inconsistent complicated effects of exercise on memory in rodents. Also, we discussed the mechanisms involved in the effects of exercise on memory processes. In addition, we tried to find scientific answers to justify the inconsistent results. In this article, the role of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (involved in synaptic plasticity and neurogenesis), and vascular endothelial growth factor, nerve growth factor, insulin-like growth factor 1, inflammatory markers, apoptotic factors, and antioxidant system was discussed in the modulation of exercise effects on memory. The role of intensity and duration of exercise, and type of memory task was also investigated. We also mentioned to the interaction of exercise with the function of neurotransmitter systems, which complicates the prediction of exercise effect via altering the level of BDNF. Eventually, we suggested that changes in the function of neurotransmitter systems following different types of exercise (depending on exercise intensity or age of onset) should be investigated in further studies. It seems that exercise-induced changes in the function of neurotransmitter systems may have a stronger role than age, type of memory task, or exercise intensity in modulating memory. Importantly, high levels of interactions between neurotransmitter systems and BDNF play a critical role in the modulation of exercise effects on memory performance.

Tramadol Treatment Induces Change in Phospho-Cyclic Adenosine Monophosphate Response Element-Binding Protein and Delta and Mu Opioid Receptors within Hippocampus and Amygdala Areas of Rat Brain.

BACKGROUND: Tramadol induces its unique effects through opioid pathways, but the exact mechanism is not known. The study aims to evaluate changes in the level of mu-opioid receptor (µOR), delta-opioid receptor (δOR), and phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB) in the hippocampus (HPC) and amygdala (AL) areas of tramadol-treated rats. METHODS: For this purpose, a total of 36 male rats were divided into two main groups for chronic or acute tramadol exposure. The animals were then exposed to 5 mg.kg-1 of tramadol, 10 mg.kg-1 of tramadol, and normal saline. The HPC and AL areas of the animals were dissected upon completion of the period. The levels of p-CREB and µOR were quantified using the western blotting technique. The data were subjected to analysis of variance (ANOVA) followed by Tukey's post-hoc analysis. The differences with the P-value lower than 0.05 were considered as significant. FINDINGS: In the HPC and AL areas of the brain, the level of µOR was decreased by acute tramadol exposure, while no significant difference was observed by chronic tramadol exposure. Moreover, results showed that the level of p-CREB dose-dependently increased by acute and chronic tramadol exposure. CONCLUSION: HPC and AL are essential in the control of tramadol abuse. Tramadol abuse affects gene expression and transcription factors such as CREB. With acute drug tramadol treatments, the level of cAMP response element-binding protein (CREB) rapidly increases, while by chronic tramadol treatment, "peak and trough pattern is observing". The activation of the rewarding mechanism is a precise instance of addictive behavior in tramadol-treated individuals.

New Biomarkers Based on Smoking-Related Phenotypes for Smoking Cessation Outcomes of Nicotine Replacement Therapy: A Prospective Study.

INTRODUCTION: Identifying a potent biomarker for smoking cessation can play a key role in predicting prognosis and improving treatment outcomes. This study aimed to evaluate the contribution of new biomarkers based on the levels of Cotinine (Cot) and carbon monoxide (CO) to the short- and long-term quit rates of nicotine replacement therapies (Nicotine Patch [NP] and Nicotine Lozenge [NL]). METHODS: In this prospective interventional study, 124 smokers under treatment with the 5A's method were selected from an outpatient smoking cessation center in district 18 of Tehran City, Iran. The study was conducted from April 2016 to December 2018. They were divided into NP (n=56) and NL (n=61) intervention groups. The levels of Cot and CO were measured using ELISA and breath analysis at the beginning of the study. Three markers were calculated: Cot/CO, Cot to cigarette per day ratio (Cot/CPD), and CO/CPD. Binary logistic regression models and generalized estimating equations models were analyzed by SPSS software, version 21 to determine the chances of quitting smoking. RESULTS: Of the NP participants, 30.4% and 19.6% were abstinent after 2 and 6 months, respectively, while NL was found less effective with 19.7% for 2-month follow-up and 13.1% for 6-month follow-up. The 6-month success of quitting attempts was significantly different for the NP participants at the second half of Cot/CO (P=0.029). Of the NL participants, CO/CPD would be a superior predictor for smoking cessation success (P>0.05). CONCLUSION: The findings of this study suggested two markers of Cot/CO and CO/CPD in this order for the optimum treatment outcomes of NP and NL.

The interaction effect of sleep deprivation and cannabinoid type 1 receptor in the CA1 hippocampal region on passive avoidance memory, depressive-like behavior and locomotor activity in rats.

Increasing evidence shows the interaction effect of cannabinoids and sleep on cognitive functions. In the present study, we aimed to investigate the interaction effect of cannabinoids type 1 receptor (CB1r) in the CA1 hippocampal region and sleep deprivation (SD) on passive avoidance memory and depressive-like behavior in male Wistar rats. We used water box apparatus to induce total SD (TSD) for 24 h. The shuttle-box was applied to assess passive avoidance memory and locomotion apparatus was applied to assess locomotor activity. Forced swim test (FST) was used to evaluate rat's behavior. ACPA (CB1r agonist) at the doses of 0.01, 0.001 and 0.0001 µg/rat, and AM251 (CB1r antagonist) at the doses of 100, 10 and 1 ng/rat were injected intra-CA1, five minutes after training via stereotaxic surgery. Results showed SD impaired memory. ACPA at the doses of 0.01 and 0.001 µg/rat impaired memory and at all doses did not alter the effect of SD on memory. AM251 by itself did not alter memory, while at lowest dose (1 ng/rat) restored SD-induced memory deficit. Both drugs induced depressive-like behavior in a dose-dependent manner. Furthermore, both drugs decreased swimming at some doses (ACPA at 0.0001 µg/rat, AM251 at 0.001 and 0.01 ng/rat). Also, ACPA at the highest dose increased climbing of SD rats. In conclusion, we suggest CB1r may interact with the effect of SD on memory. Additionally, cannabinoids may show a dose-dependent manner in modulating mood and behavior. Interestingly, CB1r agonists and antagonists may exhibit a similar effect in some behavioral assessments.

Verapamil Inhibits Mitochondria-Induced Reactive Oxygen Species and Dependent Apoptosis Pathways in Cerebral Transient Global Ischemia/Reperfusion.

The prefrontal cortex is the largest lobe of the brain and is consequently involved in stroke. There is no comprehensive practical pharmacological strategy for ameliorating prefrontal cortex injury induced by cerebral ischemia. Therefore, we studied the neuroprotective properties of verapamil (Ver) on mitochondrial dysfunction and morphological features of apoptosis in transient global ischemia/reperfusion (I/R). Ninety-six Wistar rats were allocated into four groups: control, I/R, I/R+Ver (10 mg/kg twice 1 hour prior to ischemia and 1 hour after reperfusion phase), and I/R+NaCl (vehicle). Animals were sacrificed, and mitochondrial dysfunction parameters (i.e., mitochondrial swelling, mitochondrial membrane potential, ATP concentration, ROS production, and cytochrome c release), antioxidant defense (i.e., superoxide dismutase, malondialdehyde, glutathione peroxidase, catalase, and caspase-3 activation), and morphological features of apoptosis were determined. The results showed that mitochondrial damage, impairment of antioxidant defense system, and apoptosis were significantly more prevalent in the I/R group in comparison with the other groups. Ver decreased mitochondrial damage by reducing oxidative stress, augmented the activity of antioxidant enzymes in the brain, and decreased apoptosis in the I/R neurons. The current study confirmed the role of oxidative stress and mitochondrial dysfunction in I/R progression and indicated the possible antioxidative mechanism of the neuroprotective activities of Ver.

Toxic effect of calcium/calmodulin kinase II on anxiety behavior, neuronal firing and plasticity in the male offspring of morphine-abstinent rats.

Studies have shown that epigenetic changes such as alteration in histone acetylation and DNA methylation in various brain regions play an essential role in anxiety behavior. According to the critical role of calcium/calmodulin protein kinaseII (CaMKII) in these processes, the present study examined the effect of CaMKII inhibitor (KN93) on neuronal activity and level of c-fos in the amygdala and nucleus accumbens (NAC) in the offspring of morphine-exposed parents. Adult male and female Wistar rats received morphine orally (for 21 days). After the washout period (10 days), rats were mated with either drug-naïve or morphine-exposed rats. KN93 was microinjected into the brain of male offspring. The anxiety-like behavior, the neuronal firing rate in the NAC and the amygdala and level of c-fos were assessed by related techniques. Data showed the offspring with one and/or two morphine-abstinent parent(s) had more anxiety-like behavior than the control group. However, the administration of KN-93 decreased anxiety in the offspring of morphine-exposed rats compared with saline-treated groups. The expression level of the c-fos was not significantly altered by the inhibition of CaMKII in the amygdala, but the c-fos level was reduced in the NAC. The neuronal firing rate of these groups was associated with an increase in the amygdala in comparison to the saline groups but was decreased in the NAC. Results showed that CaMKII had a role in anxiety-like behavior in the offspring of morphine-exposed parents, and changes in neuronal firing rate and c-fos level in the NAC might be involved in this process.

Tropisetron But Not Granisetron Ameliorates Spatial Memory Impairment Induced by Chronic Cerebral Hypoperfusion.

Tropisetron and Granisetorn are 5-HT3 antagonists with antiemetic effects. Tropisetron also has a partial agonistic effect on alpha-7 nicotinic acetylcholine receptors (α7 nAChRs). On the other hand, chronic cerebral hypoperfusion (CCH) attenuates cerebral blood flow and impairs cognitive functions. The goal of this study was to investigate the effect of Tropisetron and Granisetron on CCH-induced spatial memory impairment in rats. Forty-eight male Wistar rats were used in this study. 2-VO surgery was done to induce CCH and Radial Eight Arm Maz apparatus was used to evaluate spatial memory (working and reference memory). Tropisetron was injected intraperitoneally at the doses of 1 and 5 mg/kg, and Granisetron was injected intraperitoneally at the dose of 3 mg/kg. Dorsal hippocampal (CA1) neurons count, Interleukin 6 (IL-6) serum level, and serotonin-reuptake transporter (SERT) gene expression were also evaluated. The results showed, CCH impaired working and reference memory, increased IL-6 serum level, and decreased CA1 neurons and SERT expression. Tropisetron at the dose of 5 mg/kg restored all the effects of CCH. However, Granisetron did not restore CCH-induced memory impairment. Furthermore, Granisetron had no effect on IL-6. While, it increased SERT expression and CA1 neurons. In conclusion, Tropisetron but not Granisetron, ameliorated spatial memory impairment induced by CCH. We suggested conducting more detailed studies investigating the role of serotonergic system (5-HT3 receptors and serotonin transporters) and also α7 nAChRs in the effects of Tropisetron.

Curcumin prevents cognitive deficits in the bile duct ligated rats.

RATIONALE: Bile duct ligation (BDL) in rodents can cause impaired liver function and cognition deficits. Curcumin has shown a preventive and therapeutic role in memory impairment. OBJECTIVES: Therefore, this study aimed to explore the effect of curcumin on the performance of male adult Wistar rats that underwent BDL, a model of hepatic encephalopathy (HE) in the Morris water maze (MWM). METHODS: Four weeks after surgery, sham (manipulation of common bile duct without ligation) and BDL rats underwent the MWM test. RESULTS: The representative data showed that BDL rats exhibited impairments in spatial learning and reference memory in the MWM compared with the sham rats. Treatment of BDL rats with curcumin (40 mg/kg, i.p., for 4 weeks) prevented these impairments, while it did not affect spatial learning and memory in the sham rats, by itself. Curcumin increased expression levels of the pro-survival B cell lymphoma extra-large (Bcl-xL) gene and two genes involved in mitochondrial function, peroxisome proliferative-activated receptor-γ co-activator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), in the hippocampus of BDL rats compared with the vehicle-treated sham or BDL rats, while it decreased the pro-apoptotic Bcl-2-associated X protein (Bax) gene expression level. BDL up-regulated Bax and down-regulated TFAM, by itself. Furthermore, curcumin reduced the mRNA level of Bax, while it increased Bcl-2 and TFAM mRNA levels. CONCLUSIONS: These findings demonstrate the beneficial effect of curcumin on cognitive function in BDL rats of the HE model. The curcumin effect may be related to mitochondrial function improvement in the HE.

The effect of fish oil on social interaction memory in total sleep-deprived rats with respect to the hippocampal level of stathmin, TFEB, synaptophysin and LAMP-1 proteins.

Fish oil (FO) is one of the richest natural sources of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA is essential for brain functions and EPA has been approved for brain health. On the other hand, stathmin, TFEB, synaptophysin and LAMP-1 proteins are involved in synaptic plasticity, lysosome biogenesis and synaptic vesicles biogenesis. In this study, we aimed to investigate the effect of FO on social interaction memory in sleep-deprived rats with respect to level of stathmin, TFEB, synaptophysin and LAMP-1 in the hippocampus of rats. All rats received FO through oral gavage at the doses of 0.5, 0.75 and 1 mg/kg. The water box was used to induce total sleep deprivation (TSD) and the three-chamber paradigm test was used to assess social behavior. Hippocampal level of proteins was assessed using Western blot. The results showed, FO impaired social memory at the dose of 1 mg/kg in normal and sham groups. SD impaired social memory and FO did not restore this effect. Furthermore, FO at the dose of 0.75 mg/kg decreased social affiliation and social memory in all groups of normal rats, compared with related saline groups, and at the dose of 1 mg/kg impaired social memory for stranger 2 compared with saline group. In sham groups, FO at the dose of 1 mg/kg impaired social memory for stranger 2 compared with saline group. SD decreased hippocampal level of all proteins (except stathmin), and FO (1 mg/kg) restored these effects. In conclusion, FO negatively affects social interaction memory in rats.

Therapeutic potential of stem cells for treatment of neurodegenerative diseases.

Neurodegenerative diseases are caused by a loss of neurons within the peripheral or central nervous system. Inadequate repairability in the central nervous system and failure of treatments are the significant hurdles for several neurological diseases. The regenerative potential of stem cells drew the attention of researchers to cell-based therapy for treating neurodegenerative diseases. The clinical application of stem cells may help to substitute new cells and overcome the inability of the endogenous repairing system to repair the damaged brain. However, the clinical application induced pluripotent stem cells are restricted due to the risk of tumor formation by residual undifferentiated upon transplantation. In this focused review, we briefly discussed different stem cells currently being studied for therapeutic development. Moreover, we present supporting evidence for the utilization of stem cell therapy for the treatment of neurodegenerative diseases. Also, we described the key issues that should be considered to transplantation of stem cells for different neurodegenerative diseases. In our conclusion, stem cell therapy probably would be the only treatment strategy that offers a cure for neurodegenerative disease. Although, further study is required to identify ideal stem cells candidate, dosing and the ideal method of cell transplantation. We suggest that all grafted cells would be transgenically armed with a molecular kill-switch that could be activated by the event of adverse side effects.

The neuroprotective effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1α, ΔfosB and CART genes in the hippocampus of male Wistar rats.

Morphine is a natural alkaloid which derived from the opium poppy Papaver somniferum. Many studies have reported the effect of morphine on learning, memory and gene expression. CART (cocaine-amphetamine regulated transcript)is an important neuropeptide which has a critical role in physiological processes including drug dependence and antioxidant activity. ΔfosB is a transcription factor which modulates synaptic plasticity and affects learning and memory. TFAM (the mitochondrial transcription factor A) and PGC-1α (Peroxisome proliferator-activated receptor γ coactivator-1α) are critically involved in mitochondrial biogenesis and antioxidant pathways. NeuroAid is a Chinese medicine that induces neuroprotective and anti-apoptotic effects. In this research, we aimed to investigate the effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1α, ΔfosB and CART in the rat's hippocampus. In this study, Morphine sulfate (at increasing doses), Naloxone hydrochloride (2.5 mg/kg) and NeuroAid (2.5 mg/kg) were administered intraperitoneal and real-time PCR reactions were done to assess gene expression. The results showed, morphine impaired memory of step-through passive avoidance, while NeuroAid had no effect. NeuroAid attenuated (but not reversed) morphine-induced memory impairment in morphine-addicted rats. Morphine increased the expression of PGC-1α and decreased the expression of CART. However, NeuroAid increased the expression of TFAM, PGC-1α, ΔfosB and CART. NeuroAid restored the effect of morphine on the expression of CART and PGC-1α. In conclusion, morphine impaired memory of step-through passive avoidance and NeuroAid attenuated this effect. The effect of NeuroAid on morphine-induced memory impairment/gene expression may be related to its anti-apoptotic and neuroprotective effects.

Activation and Inactivation of Nicotinic Receptnors in the Dorsal Hippocampal Region Restored Negative Effects of Total (TSD) and REM Sleep Deprivation (RSD) on Memory Acquisition, Locomotor Activity and Pain Perception.

Sleep deprivation (SD) is a common issue in today's society. Sleep is essential for proper cognitive functions, including learning and memory. Furthermore, sleep disorders can alter pain information processing. Meanwhile, hippocampal nicotinic receptors have a role in modulating pain and memory. The goal of this study is to investigate the effect of dorsal hippocampal (CA1) nicotinic receptors on behavioral changes induced by Total (TSD) and REM Sleep Deprivation (RSD). A modified water box and multi-platform apparatus were used to induce TSD and RSD, respectively. To investigate the interaction between nicotinic receptors and hippocampus-dependent memory, nicotinic receptor agonist (nicotine) or antagonist (mecamylamine) was injected into the CA1 region. The results showed, nicotine at the doses of 0.001 and 0.1 µg/rat and mecamylamine at the doses of 0.01 and 0.1 µg/rat decreased memory acquisition, while both at the doses of 0.01 and 0.1 µg/rat enhanced locomotor activity. Additionally, all doses used for both drugs did not alter pain perception. Also, 24 h TSD or RSD attenuated memory acquisition with no effect on locomotor activity and only TSD induced an analgesic effect. Intra-CA1 administration of subthreshold dose of nicotine (0.0001 µg/rat) and mecamylamine (0.001 µg/rat) did not alter memory acquisition, pain perception and locomotor activity in sham of TSD/RSD rats. Both drugs reversed all behavioral changes induced by TSD. Furthermore, both drugs reversed the effect of RSD on memory acquisition, while only mecamylamine reversed the effect of RSD on locomotor activity. In conclusion, CA1 nicotinic receptors play a significant role in TSD/RSD-induced behavioral changes.

Effect of morphine exposure on novel object memory of the offspring: The role of histone H3 and ΔFosB.

It has been demonstrated that alteration in histone acetylation in the regions of the brain involved in the reward which may have an important role in morphine addiction. It is well established that epigenetic changes prior to birth influence the function and development of the brain. The current study was designed to evaluate changes in novel object memory, histone acetylation and ΔFosB in the brain of the offspring of morphine-withdrawn parents. Male and female Wistar rats received morphine orally for 21 following days. After ten days of abstinent, they were prepared for mating. The male offspring of the first parturition were euthanized on postnatal days 5, 21, 30 and 60. The novel object recognition (NOR) test was performed on adult male offspring. The amount of acetylated histone H3 and ΔFosB were evaluated in the prefrontal cortex (PFC) and hippocampus using western blotting. Obtained results indicated that the discrimination index in the NOR test was decreased in the offspring of morphine-withdrawn parents as compared with morphine-naïve offspring. In addition, the level of acetylated histone H3 was decreased in the PFC and hippocampus in the offspring of morphine-withdrawn parents during lifetime (postnatal days 5, 21, 30 and 60). In the case of ΔFosB, it also decreased in these regions in the morphine-withdrawn offspring. These results demonstrated that parental morphine exposure affects NOR memory, and decreased the level of histone H3 acetylation and ΔFosB in the PFC and hippocampus. Taken together, the effect of morphine might be transmitted to the next generation even after stop consuming morphine.

Association of microbiota-derived propionic acid and Alzheimer's disease; bioinformatics analysis.

PURPOSE: Microbiota-derived metabolites could alter the brain tissue toward the neurodegeneration disease. This study aims to select the genes associated with Propionic acid (PPA) and compromise Alzheimer's disease (AD) to find the possible roles of PPA in AD pathogenesis. METHODS: Microbiota-derived metabolites could alter the brain tissue toward the neurodegeneration disease. This study aims to select the genes associated with Propionic acid (PPA) and compromise Alzheimer's disease (AD) to find the possible roles of PPA in AD pathogenesis. RESULTS: Amongst all genes associated with PPA and AD, 284 genes to be shared by searching databases and were subjected to further analysis. AD-PPA genes mainly involved in cancer, bacterial and virus infection, and neurological and non-neurological diseases. Gene Ontology and pathway analysis covered the most AD hallmark, such as amyloid formation, apoptosis, proliferation, inflammation, and immune system. Network analysis revealed hub and bottleneck genes. MCODE analysis also indicated the seed genes represented in the significant subnetworks. ICAM1 and CCND1 were the hub, bottleneck, and seed genes. CONCLUSIONS: PPA interacted genes implicated in AD act through pathways initiate neuronal cell death. In sum up, AD-PPA shared genes exhibited evidence that supports the idea PPA secreted from bacteria could alter brain physiology toward the emerging AD signs. This idea needs to confirm by more future investigation in animal models.