Effect of combination fluoxetine and exercise on prefrontal BDNF, anxiety-like behavior and fear extinction in a female rat model of post-traumatic stress disorder (PTSD): a comparison with male animals

Abstract Despite significant differences between men and women in the symptoms of PTSD and the response to therapeutic interventions, most PTSD studies have been done on male subjects. Continuing our previous study in male rats, this study aimed at better understanding the effect of a combination therapy of exercise with fluoxetine on female PTSD rats. The results were then compared with our past findings in male animals. Female adult Wistar rats subjected to PTSD were treated with moderate treadmill exercise or fluoxetine, or a combination of both. PTSD was induced by the single prolonged stress (SPS) model. Elevated plus-maze (EPM), serum and prefrontal BDNF, and fear extinctions were evaluated. The results showed that exercise plus fluoxetine decreased anxiety-like behavior, improved fear extinction, and increased BDNF changes in female rats. The effects of exercise alone were comparable with those of combination therapy except that combination therapy was more effective on OAT (open arm entry). The majority of results in female rats, except for those of prefrontal BDNF, 4th extinction, and OAT, were similar to those of male rats as shown in our previous study. According to our findings, exercise as a safe and cost-effective intervention can be considered as a complementary efficient option for PTSD treatment in both sexes. To achieve better treatment outcomes in PTSD patient, considering sex differences is recommended

Thyroid hormones and stroke, the gap between clinical and experimental studies

Despite plenty of human studies on changes in thyroid hormones after stroke and some animal studies that assessed the effects of thyroid hormone administration on stroke, conclusive evidence for clinical application is lacking. This review aimed to determine the consistency of the results between clinical and preclinical studies. This article reviewed the PubMed, Embase, web of Knowledge, and Google Scholar databases up to June 2023 using the MeSH terms “stroke, cerebral ischemia, cerebral infarction, brain ischemia, brain infarction, triiodothyronine (T3), tetraiodothyronine (T4), thyroxine (T4), and thyroid hormone''. The results of clinical and preclinical studies related to T3 substantially confirm each other. That is, in most human studies lower T3 was associated with poor outcomes, and in experimental studies, T3 administration also had therapeutic effects. However, the results of experimental studies related to T4 could not support those of clinical studies. There seem to be some conflicts between experimental and human studies, especially regarding changes and effects of T4 after stroke. The gap between experimental and clinical studies may lead to non-applicable results, wasting time and money, and unnecessary killing of animals

Effects of Moderate Treadmill Exercise and Fluoxetine on Spatial Memory and Serum BDNF Levels in an Animal Model of Post-traumatic Stress Disorder

Background and purpose: Post-traumatic stress disorder (PTSD) develops after major trauma that is accompanied by certain signs, including pervasive fear memories, anxiety, abnormality in spatial and cognition memory, and decrease in hippocampal brain-derived neurotrophic factor (BDNF). Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PTSD. This study aimed at investigating the effects of moderate treadmill exercise and fluoxetine on spatial memory and serum BDNF levels in rat model of PTSD. Materials and methods: In this experimental study, single prolonged stress (SPS) animal model of PTSD was used. Male and female rats were divided into SPS and control groups (n=10 per group). After that, they were subjected to moderate treadmill running (5 days per week/four weeks) and fluoxetine (10 mg/kg/day). Then, behavioral assessment and BDNF measurement were done. Results: SPS male rats showed reduced spatial memory and hippocampal BDNF. Female rats showed more resistance to SPS than male rats. This may be due to the effects of gonadal hormones. The intervention alleviated the SPS-induced alterations in hippocampal-dependent spatial memory and BDNF serum levels in both male and female rats (P<0.05). Conclusion: Combined exercise and fluoxetine administration are more effective in alleviating behavioral and molecular deficits in PTSD patients

Effects of Moderate Treadmill Exercise on Anxiety and Serum Corticosterone and IGF-1 Levels in A Rat Model of Post-Traumatic Stress Disorder

Background and purpose: Post-traumatic stress disorder (PTSD (is a psychotic illness caused by different types of stressors and is associated with high economic and psychological burdens on health systems. Physiological studies of the brain have shown that serum corticosterone and insulin-like growth factor 1 (IGF-1) levels have important roles during brain damage and trauma to the nervous system. In this project, we studied the effect of exercise as an effective factor on improving anxiety and serum levels of corticosterone and IGF-1in male PTSD rats. Materials and methods: In this experimental study, single prolonged stress (SPS) was used to induce PTSD in male Wistar rats. The animals were divided into two groups: Sham (Non-SPS [NSPS]) and SPS. The two groups were then divided into two subgroups and one of the subgroups in each group did the exercise after two weeks which continued for four weeks according to the following program: moderate treadmill exercise, 5 days a week; the first two weeks 10m/min and the second two weeks 15m/min). Then, anxiety test was performed by open field test and serum levels of IGF-1 and corticosterone were measured using Eliza. Results: The rats in SPS group exhibited increased anxiety levels in open field test, decreased serum IGF-1 levels, and increased serum corticosterone levels compared with the controls. Moderate treadmill exercise alleviated SPS-induced alterations, anxiety, and IGF-1 and corticosterone levels. Conclusion: Moderate exercise could be used as a useful complementary treatment in behavioral and molecular injuries in PTSD patients

Comparing the Effect of Treadmill Exercise and Fluoxetine on Sex Hormones, Testicular Histopathology, and Fear Extinction in Adult Wistar Rats with Post-Traumatic Stress Disorder

Background and purpose: Post-traumatic stress disorder (PTSD) is a mental and physical complication. Fluoxetine (FLX) as a selective serotonin reuptake inhibitor is considered as the first line of treatment for PTSD. Exercise can improve the symptoms of PTSD. The aim of this study was to determine the effects of exercise and FLX on testicular tissue and sex hormones in rats with PTSD. Materials and methods: In this experimental study, 80 adult male rats were divided into two groups: PTSD and healthy. Then, each group was divided into four subgroups: control, exercise, fluoxetine, and fluoxetine + exercise. PTSD was induced by single prolonged stress. Fourteen days after induction of PTSD, moderate forced treadmill exercise was performed for 4 weeks, 5 days/week. Fluoxetine was administered at 10 mg/kg/day dissolved in drinking water for 4 weeks. Four weeks after treatment, the fear extinction test, testicular structure, and testosterone and FSH levels were evaluated. Results: PTSD decreased testosterone level and fear extinction but increased follicle-stimulating hormone. Fluoxetine and exercise had protective effect on testicular damage and also increased testosterone level and extinction index but decreased FSH level. Findings showed that co-administration of exercise and fluoxetine was more effective on these parameters. Combination of exercise and fluoxetine significantly increased fear extinction in PTSD rats (P<0.05). Conclusion: Exercise and fluoxetine had a protective effect on testicular tissue structure and hormonal disorders caused by PTSD and also decreased fear caused by stress, which is one of the symptoms of this disease

An Investigation of the Role of Sex Difference in the Effect of Fluoxetine on Behavioral and Biochemical Changes in Male and Female Rats Exposed to Stress

Background and purpose: Unpredictable stressors cause changes in behavioral parameters such as motor and exploratory behaviors, feeding, and sexual and anxiety behaviors. Stress leads to the release of corticosteroids and, as a result, causes dysfunction in different parts of the nervous system. A decrease in the synaptic levels of serotonin or norepinephrine in different parts of the brain such as the prefrontal cortex and a decrease in BDNF production in the hippocampus may also contribute to stress-related complications. Posttraumatic stress disorder occurs in some people after facing a severe stressful event. In PTSD, the activity and function of many physiological systems are disturbed. Fluoxetine, or Prozac, is used to treat neurological disorders such as depression and anxiety and inhibits the reuptake of serotonin by the serotonin transporter (SERT) in neurons. Some studies have shown that females respond better to SSRI antidepressants than males, which may be due to the interaction between estrogenic and serotonergic pathways. BDNF is a member of the neurotrophin family and is expressed in several tissues and cells such as the brain and blood. Its role in several mental disorders, such as depression, anxiety, eating disorders, and PTSD, has been identified. SPS (single prolonged stress) as an animal model of PTSD decreases the mRNA expression of BDNF in hippocampus rats and causes anxiety-like behaviors. The role of gender differences in the effect of antidepressants and clinical interventions in psychotic diseases is also discussed. Sex hormones in women affect the pharmacokinetics and efficacy of antidepressants. Women respond better to fluoxetine than men during reproductive years. Considering the different results regarding the effectiveness of effective drugs in the treatment of psychotic diseases in both sexes, in this study, we aim to investigate the response of male and female rats exposed to stress to the trial of fluoxetine. Materials and methods: In this experimental study, Wistar male and female rats with an average weight of 200-250 grams were used (56 animals, 8 groups of 7). The selection of the number of animals was based on previous studies in this field. After the drug intervention period, and fear and anxiety suppression test, the animals were killed under deep anesthesia, and a blood sample was collected to prepare serum to measure BDNF and corticosterone levels (using the Eliza kit of Germany Zelbio Company and according to the kit protocol). All experiments were performed according to the laboratory animal protocol of Mazandaran University of Medical Sciences. The work steps are as follows: 1. Creation of PTSD through SPS was done in three stages, 2. Drug intervention: the drug dose for all groups is 10 mg/kg/day for 4 weeks dissolved in drinking water, 3. Evaluation of anxiety-like behaviors with the light-dark box (L/D BOX), 4. Evaluation of the ability to forget painful memories with the fear silence test, 5. Measurement of BDNF and corticosterone in serum by Eliza method. Results: In this study, it was observed that male and female rats that were exposed to single prolonged stress showed a decrease in fear extinction an increase in anxiety-like behaviors in the dark-light box test, and an increase in serum corticosterone. Fluoxetine led to an increase in the percentage of fear extinction, a decrease in the Entrance Latency in the light area, the Time in the Light Compartment, the number of rearing, and a decrease in serum corticosterone significantly in both sexes(P<0.05). The change in serum BDNF levels in both sexes before and after stress was not significant. Conclusion: The results of the study showed that exposure to stress leads to behavioral and biochemical damage in male and female rats. The use of fluoxetine 10 mg/kg for 4 weeks improved the damage caused by stress, but there was a significant difference in Response of both genders to the above treatment was not observed