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.

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.

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.

Effect of treadmill exercise on serum corticosterone, serum and hippocampal BDNF, hippocampal apoptosis and anxiety behavior in an ovariectomized rat model of post-traumatic stress disorder (PTSD).

There is a sex difference in vulnerability to PTSD and in response to therapeutic interventions. Since relation between gonadal hormones and PTSD has been revealed, this study aimed to understand the severity of PTSD-induced impairments after ovarian hormone deficiency and the influence of exercise on PTSD accompanied by ovarian hormone deficiency. Female adult Wistar rats were subjected to ovariectomy, PTSD, or combination ovariectomy plus PTSD. Twenty days after ovariectomy, PTSD was induced by single prolonged stress (SPS) model. The exercise started 14 days after SPS and continued for 4 weeks. Thirty minutes moderate treadmill exercise was planned for 5 days per week. On day 65, after assessing rats using the elevated plus-maze (EPM) test, corticosterone, BDNF, and apoptotic markers were tested. p < 0.05 was considered as significant level. The results showed that ovariectomy worsened the effect of SPS on hippocampal BDNF and led to greater increase in serum corticosterone and hippocampal caspase 3 and BAX in SPS rats. Also, ovariectomy exacerbated anxiety-like behavior in SPS rats. Exercise improved the alterations of hippocampal BDNF, corticosterone, caspase 3, and BAX in SPS ovariectomized rats. However, exercise had no statistically significant effect on anxiety-like behavior in this group. According to the results, exercise is effective to attenuate SPS-induced impairments in molecular and cellular responses even when the condition becomes more complicated due to ovarian hormone deficiency. However, exercise alone cannot help to improve behavior impairments in PTSD combined with an ovarian hormone deficiency. Therefore, exercise could likely be considered as a complementary intervention to strengthen other treatments.

Effect of pre-hospital notification on delays and neurological outcomes in acute ischemic stroke.

BACKGROUND: Since timely thrombolytic therapy is a crucial variable in acute ischemic stroke recovery, health care systems are trying to find new interventions to reduce treatment delay in order to improve neurological function. In Iran, SAMA code as a pre-hospital notification plan has been developed to help emergent stroke treatment. This study aimed to compare delay to thrombolysis therapy and neurological outcomes between SAMA-transported and self-transported patients in ischemic stroke. METHODS: In this retrospective cohort study, the data of 185 stroke patients treated with intravenous thrombolysis from Mar 2016 to May 2020 were collected. P-value < 0.05 was considered as significant. RESULTS: The results showed that delays reduced in SAMA-transported patient compared to that in self-transported patients. There was a significant difference in Onset to Needle time, Door to Needle Time, and Door to CT Time but not Onset to Door time between SAMA-transported and self-transported patients (P values: 0.001, 0.000, 0.001, and 0.22 respectively). However, there was no significant difference between two groups in terms of neurologic deficit severity. CONCLUSIONS: Although pre-hospital notification could partially reduce treatment delays in stroke, that reduction was not enough to impact on neurologic deficit recovery. It seems more reduction in delay is needed to significantly improve neurological dysfunctions.

Association between GFAP-positive astrocytes with clinically important parameters including neurological deficits and/or infarct volume in stroke-induced animals.

The effect of GFAP-positive astrocytes, as positive or negative factors on stroke complications such as infarct volume and neurological deficits is currently under debate. This review was aimed to evaluate and compare the frequency of studies that showed a positive or negative relationship between astrocyte activation with the improvement of neurological deficits and/or the decrease of infarct volume. In addition, we reviewed two possible causes of differences in results including timepoint of stroke and stroke severity. Time of GFAP assessment was considered as time point and type of stroke induction and duration of stroke as stroke severity. According to our review in the most relevant English-language studies in the PubMed, Web of Science, and Google Scholar databases from 2005 to 2020, the majority of studies (77 vs. 28) showed a negative coincidence or correlation between GFAP-positive cells with neurological improvement as well as between GFAP-positive cells with infarct volume reduction. In most reviewed studies, GFAP expression was reported as a marker related to or coinciding with worse neurological function, or greater infarct volume. However, there were also studies that showed helpful effects of GFAP-positive cells on neurological function or stroke lesion. Although there are some elucidations that the difference in these findings is due to the time point of stroke and stroke severity, our review did not confirm these interpretations.

Effect of stem cells-based therapy on astrogliosis in stroke subjected-mice.

This study was planned to continue our previous study to assess effect of combination therapy bone marrow stromal cells (BMSCs) with exercise (EX) and triiodothyronine (T3) on stroke-induced astrogliosis in mice. Stroke subjected-mice were divided into five monotherapy groups including sham, control, BMSCs, EX and T3; and three combination therapy groups including BMSCs + EX, BMSCs + T3 and BMSCs + EX + T3. Astrogliosis was assessed in ipsilateral hemisphere at day 7 after MCAO. Combination therapy BMSCs with EX and T3 could significantly decrease stroke-induced astrogliosis. However, monotherapy with BMSCs or EX also improved changes of glial fibrillary acidic protein (GFAP)-positive cells following stroke. Combination therapy BMSCs with EX and T3 didn't have any added effect on astrogliosis compared to monotherapy with BMSCs or EX. With comparing the present findings with the results of neurobehavioral functioning in our earlier study, it seems that decrease of astrogliosis could be helpful for stroke recovery.

Occurrence of priapism after transient right MCAO in Swiss albino mice.

Introduction: There are few reports about sexual problems in animal models after stroke. The aim of this paper is to report the occurrence of priapism after right MCAO in Swiss albino mice. In addition, we compared neurological score and apoptosis between the priapism-affected and unaffected mice. Methods: Swiss albino mice were subjected to 45 min' MCAO and 7 days' reperfusion. Mice were observed before MCAO, then daily for 7 days to assess priapism. Neurological status and apoptosis (TUNEL assay) were assessed and compared in priapism and non-priapism mice. Results: The results showed that the incidence of priapism after MCAO in Swiss albino mice were 65%. Priapism was detectable often at day 2 after stroke. Priapism-affected group had more severe behavioural deficits after stroke compared to non-priapism stroke mice. Conclusion: Priapism after right MCAO is not rare in albino mice and could be considered as a marker of stroke severity. Further studies are needed to assess the incidence of priapism after stroke in other animal species used for stroke studies such as rat.

Bone Marrow Stromal Cells With Exercise and Thyroid Hormone Effect on Post-Stroke Injuries in Middle-aged Mice.

INTRODUCTION: Based on our previous findings, the treatment of stem cells alone or in combination with thyroid hormone (T3) and mild exercise could effectively reduce the risk of stroke damage in young mice. However, it is unclear whether this treatment is effective in aged or middle-aged mice. Therefore, this study designed to assess whether combination of Bone Marrow Stromal Cells (BMSCs) with T3 and mild treadmill exercise can decrease stroke complications in middle-aged mice. METHODS: Under laser Doppler flowmetry monitoring, transient focal cerebral ischemia was produced by right Middle Cerebral Artery Occlusion (MCAO) for 45 min followed by 7 days of reperfusion in middle-aged mice. BMSCs (1×105) were injected into the right cerebral ventricle 24 h after MCAO, followed by daily injection of triiodothyronine (T3) (20 µg/100 g/d SC) and 6 days of running on a treadmill. Infarct size, neurological function, apoptotic cells and expression levels of Glial Fibrillary Acidic Protein (GFAP) were evaluated 1 week after stroke. RESULTS: Post-ischemic treatment with BMSCs or with T3 and or mild treadmill exercise alone or in combination did not significantly change neurological function, infarct size, and apoptotic cells 7 days after ischemia in middle-aged mice (P>0.05). However, the expression of GFAP significantly reduced after treatment with BMSCs and or T3 (P<0.01). CONCLUSION: Our findings indicate that post-stroke treatment BMSCs with exercise and thyroid hormone cannot reverse neuronal damage 7 days after ischemia in middle-aged mice. These findings further support that age is an important variable in stroke treatment.

Effects of the Oral Ingestion of Probiotics on Brain Damage in a Transient Model of Focal Cerebral Ischemia in Mice.

BACKGROUND: Probiotics are microorganisms that may influence brain function via altering brain neurochemistry. New research evidence suggests that probiotic bacteria might protect tissue damage through diminishing the production of free radicals and/or inflammatory cytokines. Therefore, this study was designed to evaluate the effects of probiotic bacteria on the prevention or reduction of brain damage in an experimental model of stroke in mice. METHODS: In this study, 30 male BLC57 mice were randomly divided into 6 equal groups. Focal cerebral ischemia was induced via middle cerebral artery occlusion for 45 minutes, followed by 24 hours of reperfusion, in the mice. Probiotics at a concentration of 107 CFU/mL were administered by oral gavage daily for 14 days before ischemia. Infarct size, neurological outcome, and biochemical markers were measured 24 hours after brain ischemia. Statistical analysis were performed using the one-way ANOVA and/or Kruskal-Wallis ANOVA on rank by Sigma Stat (2.0; Jandel Scientific) software. RESULTS: Our results indicated that pretreatment with probiotics significantly reduced infarct size by 52% (P=0.001) but could not improve neurological function (P=0.26). Moreover, the administration of probiotics significantly decreased the malondialdehyde content (P=0.001) and the tumor necrosis factor-alpha level (P=0.004) in the ischemic brain tissue. CONCLUSION: The findings of the present study showed that probiotic supplements might be useful in the prevention or attenuation of brain ischemic injury in patients at risk of stroke. Probiotics may open new therapeutic alternatives for the prevention of stroke. More preclinical and clinical studies are, however, needed to clarify their efficacy in cerebral stroke.