Treadmill Exercise Improves Behavioral and Neurobiological Alterations in Restraint-Stressed Rats.

Stress is a state that is known to impact an organism's physiological and psychological balance as well as the morphology and functionality of certain brain areas. In the present work, chronic restraint stress (CRS) model rats treated with treadmill exercise were used to examine anomalies associated to emotion and mood as well as molecular changes in the brain. Forty male Sprague-Dawley rats were divided into control, stress, exercise, and stress+exercise groups. CRS were exposed to stress group rats and exercise group underwent a chronic treadmill exercise. Depressive-like behavior was evaluated with the forced swim test (FST) and tail suspension test (TST). For assessing anxiety-like behavior, the light-dark test (LDT) and the open field test (OFT) were used. The Morris water maze test (MWMT) was used for testing memory and learning. Brain's monoamine level and the expression of genes related to stress were measured. It was discovered that CRS lengthens latency in the MWMT, increases immobility in the FST and TST, decreases time in the light compartment, and causes hypoactivity in the OFT. CRS reduced the dopamine levels in the nucleus accumbens(NAc). Brain-derived neurotrophic factor (BDNF), dopamine receptors, and serotonin receptor (HTR2A) gene expression in the prefrontal cortex, corpus striatum, and hypothalamus were decreased by CRS. Exercise on a treadmill leads to increase NAc's dopamine and noradrenaline levels and prevented behavioral alterations. Exercise increased the alterations of BDNF expressions in the brain in addition to improving behavior. As a result, CRS-induced behavioral impairments were effectively reversed by chronic treadmill exercise with molecular alterations in the brain.

Effects of acute aerobic exercise on brain-derived neurotrophic factor level in rheumatoid arthritis patients.

Objectives: The study aimed to investigate the variation of brain-derived neurotrophic factor (BDNF) levels following acute exercise in patients with rheumatoid arthritis (RA). Patients and methods: This cross-sectional study was conducted with 88 participants (25 males, 63 females; mean age: 45.1±8.3 years; range, 18 to 65 years) between July 2020 and May 2021. Of the participants, 44 were RA patients, and 44 were age-and sex-matched healthy controls. Aerobic exercise was utilized in all participants for a single session. Depression and anxiety levels were evaluated with the Beck Depression Inventory and Hospital Anxiety and Depression Scale. Blood samples were collected from all subjects before and immediately after the intervention. Results: Serum BDNF levels (both baseline and after exercise) were similar in the RA and control groups. Although serum BDNF levels significantly decreased in both groups after aerobic exercise (Wilcoxon rank p<0.05), ΔBDNF levels were significantly higher in the RA group than in the control group (p=0.047). Additionally, ΔBDNF levels were significantly correlated with the Hospital Anxiety and Depression Scale scores in the RA group (p<0.05) but not in the control group. Conclusion: A single bout of exercise may effectively decrease serum BDNF levels in patients with RA and healthy subjects. The long-term effect of exercise on BDNF levels should be investigated in prospective studies.

TRPM2 may be involved in high fructose corn syrup-induced anxiety-like behavior in adult male rats.

Excessive high fructose corn syrup (HFCS) consumption is known to cause oxidative stress, which induces transient receptor potential melastatin type 2 (TRPM2) channel gating. Oxidative stress-induced TRPM2 gating is suggested to play an important role in neurons, indicating a role for the TRPM2 channel in a variety of neuropsychiatric disorders including depression and anxiety. We investigated the effects of HFCS and chronic immobilization stress (CIS) on TRPM2 channel immunoreactivity, anxiety, and depressive-like behaviors in adult male rats. The male rats (n=8/group) were divided into 4 groups: Control, 20% HFCS (F20), 40% HFCS (F40), and stress. The control group received tap water, and F20 and F40 groups were exposed to HFCS 20% and 40% respectively for 14 consecutive days. Rats in the stress group were subjected to immobilization stress for 3 or 6 hours daily in the first and second weeks to induce CIS. Then, light/dark tests, open field tests (OFT), and tail suspension tests (TST) were performed, respectively. In the light/dark test, the time spent in the dark chamber significantly increased in all groups vs the control group (P<0.01). In support of this result, time spent in the light chamber significantly decreased in all groups vs the control group (P<0.01). Besides, CIS significantly increased depressive-like behavior in the stress group vs the control group (P<0.05). In serum hormone levels, corticosterone (CORT) levels significantly increased in the F40 and stress groups vs the control group (P<0.01). TRPM2 immunoreactivity significantly increased in the hippocampus, prefrontal cortex (PFC), nucleus accumbens (NaC), and amygdala regions by HFCS and CIS treatments. For the first time in the present study,  showed that f increased immunoreactivity of the TRPM2 cation channels may be linked to the anxiety-like behavior induced by HFCS.

Treadmill exercise has healing effects on obesity-induced sexual behavior disorder through kisspeptin and kiss1R expression in male rats.

The basic objective of this study was to examine the possible effects of treadmill exercise on obesity-related sexual behavior disorder in obese male rats and the role of kisspeptin in this effect. The rats were separated from their mothers at the age of 3 weeks, and classified into four groups as Control (C): normal diet-sedentary group, Exercise (E): normal diet-exercise group, Obese (O): high-fat diet-sedentary group, Obese + Exercise (O+E): high-fat diet-exercise grouSexual behavioral testing was conducted in the rats. At the end of the study, brain samples were taken from the animals for gene expression analyses. The treadmill exercise caused a significant increase in the O+E Group compared to the O Group in kisspeptin and kiss1R gene expression and in EF, ML, IL, MF, IF, III, EL, PEI, IR1, MFT, IFT, IRT sexual behavior parameters (p<0.05), and a significant decrease in ML, IL, III, EL sexual behavior parameters (p<0.05). Treadmill exercise caused a significant decrease in EF, ML, IL, MF, IF, III, EL, PEI, IR1, MFT, IFT, IRT sexual behavior parameters and kisspeptin and kiss1R gene expression in the hypothalamus, hippocampus, prefrontal cortex and corpus striatum in E Group compared to C Group (p<0.05), and a significant increase in ML, IL, III, EL sexual behavior parameters (p<0.05). Based on this effect, we believe that it is caused by an increase in kisspeptin and kiss1R expression in the hypothalamus, hippocampus, prefrontal cortex and corpus striatum. In conclusion, treadmill exercise-induced kisspeptin secretion may increase GnRH secretion and cause hypothalamo-pituitary gonadal axis activation and ameliorative effect on deteriorated sexual function.

Effects of acute aerobic exercise on cytokines, klotho, irisin, and vascular endothelial growth factor responses in rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes cartilage and bone damage as well as disability.  AIMS : The aim of this study was to examine the effects of acute aerobic exercise on cytokines such as serum interleukin-6 (IL-6), interleukin-1ß (IL-1ß), Tumor Necrosis Factor-α (TNF-α) and irisin, vascular endothelial growth factor(VEGF) and klotho in RA patients.  METHODS: Forty RA patient and 40 healthy volunteers of the same age participated in this study. All participants walked on the treadmill for 30 minutes at 60-80% of maximal heart rate. Blood samples were taken before and immediately after the exercise. Serum levels of IL-6, IL1ß, TNF-α and irisin, VEGF and klotho were measured by enzyme-linked immunosorbent analysis.  RESULTS: Baseline levels of inflammatory cytokines, irisin, VEGF and klotho were found to be higher in RA patients compared to the control group. In both groups, there was an increase in serum klotho levels after exercise compared to baseline (p<0.05), while a decrease in IL1ß, TNF-α levels were observed. While serum VEGF level decreased in RA group, it increased in the control group(p<0.05). Irisin levels decreased in both groups. IL-6 level did not change in the control group, while it increased in RA group. A single exercise session had an acute anti-inflammatory effect in RA patients. CONCLUSION: It can be concluded that acute aerobic exercise can be beneficial for patients with RA through cytokine, irisin, klotho and VEGF levels, and also it can be safely implemented to the RA rehabilitation program for additional anti-inflammatory effects. Trial registration ClinicalTrials.gov: NCT04439682.

The Effect of Irisin on Thyroid Hormone Levels in Chronic Paroxetine-Treated Rats.

It is known that serotonin reuptake inhibitors (SSRIs), which are widely used in mood disorders, affect the hypothalamic-pituitary-thyroid axis activity. In this study, we investigated the effect of paroxetine, an SSRI, on thyroid hormone levels in rats. We also examined the role of irisin, a newly discovered potential regulatory hormone for metabolism, on paroxetine-induced changes. A total of 64 Sprague-Dawley female and male rats were randomly divided into four subgroups for each gender and treated as follows: sham-operated control (vehicle), paroxetine (treated with 20 mg/kg paroxetine by oral gavage), irisin (100 ng/kg/day for 28 days with mini-osmotic pumps), and paroxetine + irisin group (n = 8). Serum fasting free triiodothyronine (fT3) and free thyroxine (fT4) levels were measured by automated chemiluminescence method. Serum thyroid-stimulating hormone (TSH) level was determined with enzyme-linked immunosorbent analysis (ELISA). Compared to the sham control group (p < 0.05), the significantly reduced fT4 and TSH serum levels in paroxetine-treated male animals were markedly increased by subcutaneous irisin perfusion. fT3 levels significantly increased in both irisin (4.35 ± 0.17 pq/mL) and paroxetine + irisin groups (4.51 ± 0.19 pq/mL) compared to sham control (3.60 ± 0.23 pq/mL) and paroxetine groups (3.57 ± 0.12 pq/mL) (p < 0.05). It was observed that serum fT3, fT4, and TSH levels decreased in female animals receiving paroxetine compared to the sham control group. Subcutaneous administration of irisin increased these hormone levels. However, these changes were not statistically significant. These results suggested that irisin may play a role in the mechanism underlying the beneficial effects of exercise in preventing SSRI-related side effects by increasing thyroid hormone levels, which were decreased by paroxetine.

Treadmill exercise training improves the high-fat diet-induced behavioral changes in the male rats.

The purpose of this study was to investigate the effects of treadmill exercise training on obesity-induced behavioral changes in high-fat diet (HFD)-induced male rats. In this study, 40 male Sprague-Dawley rats were divided into 4 groups after they were weaned: Control (C), Exercise (E), Obese (O) and Obese + Exercise (O + E). For the obesity model % 60 high-fat diet were applied. After obesity was induced, rats were either moderate aerobic exercise (treadmill running) trained or left untrained. Different tasks to assess spatial learning and memory (Morris water maze test (MWMT)), depressive-like behavior (forced swimming test(FST), tail suspension test (TST) and anxiety-like behavior (light-dark test (LDT) and open field test (OFT)) were conducted. Exercise caused a significant reduction in duration of immobility in the O group in FST and the decrease in immobility in the O + E rats in TST. The O + E rats demonstrated a significant increase in the time spent in the light box as compared to the O group in the LDT. The O + E rats did not show any behavioral alterations as compared to all the other groups in the OFT. In the O + E group, there was a significant increase in the time spent in the target quadrant compared to the O group in the MWMT. Our results support that treadmill exercise could improve cognitive, depressive-like, anxiety-like behavioral changes in the HFD-induced obese rats.

Combined progressive functional exercise effect on contactin-1 and contactin-2 level in mildly disabled persons with multiple sclerosis.

BACKGROUND: Although contactin-1 and contactin-2 are known as two proteins involved in axonal regeneration, it is unclear whether these proteins are induced by exercise in persons with multiple sclerosis (PwMS). OBJECTIVE: The aim of this study was to determine the serum levels of contactin-1 and contactin-2 in PwMS and to investigate the change of these markers with exercise. METHODS: A total of 60 participants with relapsing-remitting MS were divided into groups by stratified randomization. The progressive functional exercise was applied to the intervention group. Participants in the control group continued the treatments and lives of the routines. Participants' contactin-1 and contactin-2, cognitive performance and aerobic capacities were evaluated. RESULTS: The comparison of the pre-and post-study values of contactin-1 and contactin-2 showed significant differences only in the intervention group. The contactin-1 and contactin-2 values were similar between the groups before the exercise, whereas a significant difference was found in favor of the intervention group after the exercise. Paced Auditory Serial Addition Test-3 value increased significantly only in the intervention group. CONCLUSION: With this study, it was shown for the first time that contactin-1 and contactin-2, which play an important role in axonal regeneration and axonal organization, can be increased by exercise.

Aerobic exercise increases irisin serum levels and improves depression and fatigue in patients with relapsing remitting multiple sclerosis: A randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease of the central nervous system. Although there is increasing evidence that aerobic exercise has a positive effect on both cognitive and psychological functioning, there is limited evidence for Relapsing-Remitting MS (RRMS) patients. Moreover, it is unclear at what exercise modality and intensity the irisin, the cleaved and circulating form of the exercise-associated membrane protein Fibronectin Type III Domain Containing 5, is induced in patients with MS. This study aimed to investigate the effect of a regular aerobic exercise program on irisin serum level, depression, fatigue, and cognitive performance in patients with MS. METHODS: Thirty-two individuals with RRMS were randomized into 2 groups as control and study groups (mean EDSS score 1.69 and 1.97, respectively). While the Study Group received a combined exercise training consisting of three sessions of aerobic exercise and Frenkel Coordination Exercises per week for 6 weeks, the Control Group received only Frenkel Coordination Exercise training. Before and after the study, the cognitive performance of the participants were evaluated with the Paced Auditory Serial Addition Test with 3-second stimulus (PASAT-3), their maximum aerobic capacity with the Fitmate Pro® (VO2max), their fatigue status with the Fatigue Impact Scale (FIS), and their depression status with the Beck Depression Inventory (BDI). Irisin serum levels were analyzed with Enzyme-Linked ImmunoSorbent Assay (ELISA) test from the serum samples of individuals. RESULTS: Our results revealed that the irisin serum level significantly increased in the Study Group. Significant improvement in aerobic capacity, PASAT-3, FIS, and BDI values was observed in the Study Group compared to the Control Group. When the ΔIrisin, ΔVO2max, ΔFIS, and ΔBDI values between the groups were compared, a significant difference was found in favor of the study group. CONCLUSION: The aerobic exercise revealed significant changes in depression, fatigue and irisin serum levels in MS patients. We think that this study, in which a significant increase in irisin serum level, significant improvement in depression, cognitive performance and fatigue states were obtained in the Study Group, will be a pioneering study for the future studies aiming to investigate the effects of irisin serum level on these symptoms in detail.

Beneficial effects of irisin in experimental paroxetine-induced hyperprolactinemia.

OBJECTIVE: It is known that selective serotonin reuptake inhibitors (SSRIs), represent an important and effective treatment of depression and other psychological disorders, these medications can increase prolactin levels mainly through activation of the serotonergic pathway. In this study, we aimed to determine the beneficial effects of irisin on paroxetine, a SSRI, induced hyperprolectinemia and in some other reproductive hormonal changes associated with hyperprolactinemia. METHODS: Thirty two male Spraque-Dawley rats were used and divided into four groups including sham-operated control (vehicle), irisin (100 ng/kg/day for 28 days with mini-osmotic pumps), paroxetine (treated with 20 mg/kg paroxetine by oral gavage), irisin and paroxetine+irisin groups (n = 8). Serum prolactin (PRL), kisspeptin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and 5-alpha reductase levels were determined with enzyme-linked immunosorbent analysis (ELISA). RESULTS: In animals treated with paroxetine, PRL level increased and testosterone level decreased significantly (p < 0.05). Serum LH level was significantly increased in the group, but no significant changes were observed in the FSH, kisspeptin and 5-alpha reductase levels. Serum prolactin levels was significantly decreased in the group treated with irisin. While no significant difference was observed in kisspeptin, FSH and 5-alpha reductase levels, an increase in serum LH and testosterone levels with irisin administration (p < 0.05). CONCLUSION: In conclusion, chronic irisin exposure may reverse paroxetine-induced hyperprolactinemia. These results indicate that irisin may have the potential to be used as a therapeutic agent by primarily affecting paroxetine-induced increased prolactin and decreased testosterone levels.

The effect of aerobic exercise on Neurofilament light chain and glial Fibrillary acidic protein level in patients with relapsing remitting type multiple sclerosis.

Background Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system in which disease activity can be monitored with some biomarkers. The aim of our study was to investigate serum Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Light Chain (NFL) in relapsing-remitting MS (RRMS) patients after the aerobic exercise. Methods A total of 38 participants with RRMS (Expanded Disability Status Scale: 1.0 - 4.5) were randomized to a study group (3 × /week for 8 weeks at 60 - 70 % of maximal aerobic capacity (VO2max) + home exercises) and a control group (were given home exercises programme 3 times a week for 8 week). Serum NFL and GFAP levels were analyzed using enzyme-linked immunosorbent analysis method before and at the end of 8 weeks. Results: NFL and GFAP levels were statistically lower in the study group at the end of the study than before the study. In the control group, no significant changes were observed in serum NFL and GFAP levels. ΔNFL levels were significantly higher in the study group than control group. Conclusion It was shown, for the first time that serum GFAP and NFL levels (%10 and % 32, respectively) in RRMS patients decreased after aerobic exercise. Our study is important in terms of investigating the effects of aerobic exercise in individuals with RRMS and elucidating the underlying measurable biomarkers. The significant reduction of NFL and GFAP, which have an important role in the pathology associated with nervous system damage in MS, with aerobic exercise may be promising in understanding the regulation of disease activity in MS patients.

The Evaluation of Radiologic Angular Measurements in Patients with Foot Pain.

BACKGROUND: The aim of this study was to investigate the relationship between foot deformities by comparing foot radiographs of patients with complaints of foot pain with those of healthy individuals. METHODS: The study included 30 patients with pes cavus, 30 patients with pes planus, 30 patients with calcaneal spur, and 30 controls aged 30 to 60 years. All participants underwent measurement of right and left foot length; metatarsophalangeal width; and calcaneal pitch (CA), talohorizontal (TA), talometatarsal (TM), and lateral talocalcaneal (LTC) angles from lateral radiographs. RESULTS: There were no statistically significant differences between all participants regarding sex, age, weight, and body mass index (P > .05). Among patients with clinically diagnosed pes cavus, the diagnostic rate of CA was 100% in both feet, and 83.3% in the right foot and 96.7% in the left foot according to the TM angle. The diagnostic rates of angular measurements in patients with pes planus were as follows: 20% in the right foot and 30% in the left foot depending on the CA angle, 100% in both feet depending on the TM angle, and 66.7% in the right foot and 46.7% in the left foot depending on the LTC angle. A very strong positive correlation was found between the CA and LTC angles in patients with calcaneal spur and pes planus (P < .001); also, statistically significant positive correlation was found between the CA and TA angles (P < .05). The angular measurements in patients with calcaneal spur were found to be consistent with pes planus with a high rate. CONCLUSIONS: Angular changes caused by deterioration of foot biomechanics lead to various deformities. Pes planus ranks first among these. Therefore, we believe that radiographic angular measurements in patients presenting with foot pain in addition to clinical evaluation would be useful in considering associated deformities and planning treatments.

The effect of additional neuromuscular electrical stimulation applied to erector spinae muscles on functional capacity, balance and mobility in post-stroke patients.

OBJECTIVE: The aim of this study was to investigate the effects of neuromuscular electric stimulation applied to the erector spinae on balance, motor function and functional capacity in patients with stroke in a randomized controlled trial. METHODS: Sixty patients with stroke were recruited and randomly distributed into two groups: control group and neuromuscular electric stimulation group. All participants underwent conventional physical therapy five times a week for six weeks. The neuromuscular electric stimulation group received additional electrical stimulation. Outcome measures were evaluated with Brunnel Balance Assessment, Stroke Rehabilitation Movement Assessment, Functional Ambulation Classification, Adapted Patient Evaluation and Conference System, Postural Assesment Scale for Stroke patients, Short Form-36, and Minimental State Examination scales. RESULTS: Significant differences were observed in all scores at the end of the study in both groups. Postural Assesment Scale for Stroke patients and Stroke Rehabilitation Movement Assessment scores were higher in the neuromuscular electric stimulation group compared to the control group (p < 0.05). All the other scores were not statistically significant. CONCLUSION: It is recommended to evaluate and treat trunk muscle, which is usually neglected in treatment, and to consider the combination of conventional treatment and neuromuscular electric stimulation when designing an ideal rehabilitation program.

The effects of apelin on myometrium contractions in pregnant rats.

Apelin, which is a new hormone, is secreted especially in the brain by hypothalamus as well as by many other organs like the stomach, fat tissue, and the heart. For apelin, whose possible effects on many bodily functions like the endocrine system, cardiovascular system and metabolic activities are still under investigation, the reproductive system is also an important target area. The purpose of the present study was to investigate the effects of plasma apelin levels in rats that were in diestrus, pregnancy and lactation periods, and to examine its possible effects on myometrium contractions of pregnant rats and non-pregnant rats that were in diestrus period.  The plasma apelin concentrations in female adult Wistar rats were determined with the ELISA method in the diestrus period, and on the 12th, 18th, and 21st days of the pregnancy, and on the 2nd and 10th days of lactation (n=7 for each group). In addition, the effect of apelin at 0.01, 0.1, 1 and 10 µM doses on isometric contractions in the rat uterus on the 21st day of pregnancy and in diestrus period was tested by using isolated organ bath. This protocol was repeated under conditions that were pre-treated with protein kinase C inhibitor in calcium-free medium, and the possible effect of apelin on contractions and the mechanisms that might mediate this effect were investigated. When plasma apelin levels were compared with the rats in diestrus period, the apelin concentrations in the 21-day pregnancy group were high at a significant level (p<0.05); and low at a significant level in the 2-day lactation group (p<0.05). In myometrium contraction trials, it was observed that apelin induced the contractions. Apelin increased the frequency of the myometrium contractions at a significant level when applied at 1 µM and 10 µM concentrations (p<0.05 and p<0.001). Only after the apelin application at 10 µM concentration did the amplitude of the contractions increase at a significant level (p<0.01). In the myometrium of the rats that were on the 21st day of pregnancy, the frequency of the contractions was statistically significant at 0.1 µM, 1 µM and 10 µM doses (p<0.01). In addition, the amplitude of the contractions increased at a statistically significant level at 1 µM and 10 µM dose application (p<0.05 and p<0.01, respectively). The apelin application induced the contractions in calcium-free medium. When apelin was applied after the pre-application with protein kinase C inhibitor, no contractions were observed. The present study showed that apelin levels were increased at the end of pregnancy in rats, and the hormone induced the uterus contractions. This effect does not occur with protein kinase C inhibitor and in calcium-free medium, which shows that protein kinase C pathway might play a role in these mechanism.  These findings show that apelin might be an endogenous peptide that plays a role on uterine contractions at birth in rats.

Studies on the reproductive effects of chronic treatment with agomelatine in the rat.

Agomelatine is an antidepressant with a novel mechanism of action. It is a melatonergic agonist for MT1 and MT2 receptors and a serotonin (5-HT2C) receptor antagonist. Agomelatine has been suggested not to have adverse effects on sexual functions. However, the effects of chronic agomelatine administration on reproductive functions have not been sufficiently studied in animal models. We mainly aimed to explore the effects of agomelatine on reproductive functions in the male and female rats. For the experimental studies, Sprague Dawley rats were used. The animals started to receive daily oral agomelatine (10mg/kg) on post-natal day 21. Agomelatine advanced vaginal opening in the female rats whereas it delayed puberty onset in the male rats. Agomelatine treatment significantly decreased intromission frequencies, which indicates a facilitator role of this antidepressant on male sexual behavior. In the forced swimming test (FST) used for assessing antidepressant efficacy, agomelatine induced a significant decrease in duration of immobility, and an increase in the swimming time, respectively, which confirms the antidepressant-like activity of agomelatine. The present findings suggest that agomelatine shows a strong antidepressant effect in the male rats without any adverse influences on sexual behavior, and its effects on pubertal maturation seem to show sex-dependent differences.