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.

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.

The effect of Crocin on TFAM and PGC-1α expression and Catalase and Superoxide dismutase activities following cholestasis-induced neuroinflammation in the striatum of male Wistar rats.

Bile secretion is a physiological function that is disrupted following Bile Duct Ligation (BDL) and induces cholestasis. Cholestasis is a bile flow reduction that induces apoptosis, oxidative stress, and inflammation, and alters the expression of genes. Evidence shows the relationship between cholestasis and neuroinflammation. Cholestasis via attenuating mitochondrial biogenesis and anti-oxidant activity can induce neuroinflammation and apoptosis. Mitochondrial transcriptional factor A (TFAM) and Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are involved in mitochondrial biogenesis, and TFAM, PGC-1α, Catalase (CAT), and Superoxide dismutase (SOD) have a role in upregulating antioxidant pathways. On the other hand, many studies have shown the neuroprotective effects of Crocin, the water-soluble carotenoid of Saffron (Crocus sativus L.). In this study, we aimed to investigate the effect of Crocin on the level of TFAM, PGC-1α, CAT, and SOD following cholestasis-induced neuroinflammation in the rat's striatum. Cholestasis was induced by BDL surgery and administration of Crocin was intraperitoneal, at the dose of 30 mg/kg every day, 24 h after BDL surgery up to thirty days. The results showed that TFAM, PGC-1α, and SOD were decreased following cholestasis; while, CAT was increased. In addition, Crocin restored the effects of cholestasis on the level of TFAM, PGC-1α, and SOD. In conclusion, Crocin may have improvement effects on cholestasis-induced neuroinflammation in the rat's striatum.

The Effect of NeuroAid (MLC901) on Cholestasis-Induced Spatial Memory Impairment with Respect to the Expression of BAX, BCL-2, BAD, PGC-1α and TFAM Genes in the Hippocampus of Male Wistar Rats.

Cholestasis is a bile flow reduction that is induced following Bile Duct Ligation (BDL). Cholestasis impairs memory and induces apoptosis. Apoptosis consists of two pathways: intrinsic and extrinsic. The intrinsic pathway is modulated by BCL-2 (B cell lymphoma-2) family proteins. BCL-2 (a pro-survival BCL-2 protein) has anti-apoptotic effect, while BAD (BCL-2-associated death) and BAX (BCL-2-associated X), the other members of BCL-2 family have pro-apoptotic effect. Furthermore, TFAM (mitochondrial transcriptional factor A) is involved in transcription and maintenance of mitochondrial DNA and PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) is a master regulator of mitochondrial biogenesis. On the other hand, NeuroAid is a Traditional Chinese Medicine with neuroprotective and anti-apoptosis effects. In this study, we evaluated the effect of cholestasis on spatial memory and expression of BCL-2, BAD, BAX, TFAM, and PGC-1α in the hippocampus of rats. Additionally, we assessed the effect of NeuroAid on cholestasis-induced cognitive and genetic alterations. Cholestasis was induced by BDL surgery and NeuroAid was injected intraperitoneal at the dose of 0.4 mg/kg. Furthermore, spatial memory was evaluated using Morris Water Maze (MWM) apparatus. The results showed cholestasis impaired spatial memory, increased the expression of BAD and BAX, decreased the expression of TFAM and PGC-1α, and did not alter the expression of BCL-2. Also, NeuroAid decreased the expression of BAD and BAX and increased the expression of TFAM, PGC-1α, and BCL-2. In conclusion, cholestasis impaired spatial memory and increased the expression of pro-apoptotic genes. Also, cholestasis decreased the expression of TFAM and PGC-1α. Interestingly, NeuroAid restored the effects of cholestasis.

Effects of Treadmill Exercise on the Expression Level of BAX, BAD, BCL-2, BCL-XL, TFAM, and PGC-1α in the Hippocampus of Thimerosal-Treated Rats.

Thimerosal (THIM) induces neurotoxic changes including neuronal death and releases apoptosis inducing factors from mitochondria to cytosol. THIM alters the expression level of factors involved in apoptosis. On the other hand, the anti-apoptotic effects of exercise have been reported. In this study, we aimed to discover the effect of three protocols of treadmill exercise on the expression level of mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), BCL-2-associated death (BAD), BCL-2-associated X (BAX), BCL-XL, and BCL-2 (a pro-survival BCL-2 protein) in the hippocampus of control and THIM-exposed rats. Male Wistar rats were used in this research. Real-time PCR was applied to assess genes expression. The results showed that THIM increased the expression of pro-apoptotic factors (BAD and BAX), decreased the expression of anti-apoptotic factors (BCL-2 and BCL-XL), and decreased the expression of factors involved in mitochondrial biogenesis (TFAM and PGC-1α). Treadmill exercise protocols reversed the effect of THIM on all genes. In addition, treadmill exercise protocols decreased the expression of BAD and BAX, increased the expression of BCL-2, and increased the expression of TFAM and PGC-1α in control rats. In conclusion, THIM induced a pro-apoptotic effect and disturbed mitochondrial biogenesis and stability, whereas treadmill exercise reversed these effects.

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.

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.

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 cholestasis and NeuroAid treatment on the expression of Bax, Bcl-2, Pgc-1α and Tfam genes involved in apoptosis and mitochondrial biogenesis in the striatum of male rats.

Cholestasis means impaired bile synthesis or secretion. In fact, it is a bile flow reduction following Bile Duct Ligation (BDL). Cholestasis has a main role in necrosis and apoptosis. Apoptosis is a form of programmed cell death that has intrinsic and extrinsic pathways. The intrinsic pathway is mediated by Bcl-2 (B cell lymphoma-2) proteins which integrate death and survival signals. Bcl-2 has anti-apoptotic and Bax has pro-apoptotic effects. Also, striatum is one of the brain regions that has high expressions of Bcl-2 proteins. Moreover, Tfam and Pgc-1α are involved in mitochondrial biogenesis. On the other hand, NeuroAid, is a drug that has neuroprotective and anti-apoptosis effects. In this study, using quantitative PCR, we measured the expression of all these genes in the striatum of male rats following BDL and NeuroAid administration. Results showed, BDL increased the expression of Bax and Tfam and decreased the expression of Bcl-2. NeuroAid restored the effect of BDL on the expression of Bax, while did not alter the effect of BDL on Bcl-2. In addition, it increased the expression of Tfam that was previously elevated by BDL and raised the expression of Tfam in normal rats. Both BDL and NeuroAid, had no effect on Pgc-1α. In conclusion, cholestasis increased the expression of Bax and decreased the expression of Bcl-2, and this effect may have related to enhanced susceptibility of mitochondrial pathways following oxidative stress. Tfam expression was increased following cholestasis and this effect may have related to cellular compensatory mechanisms against high accumulation of free radicals or mitochondrial biogenesis failure. Furthermore, NeuroAid may play a role against apoptosis and can be used to increase mitochondrial biogenesis.