Alternating mealtimes during pregnancy and weaning triggers behavioral changes in adult offspring.

In brief: Mealtime changes in pregnant mice revealed impaired neurobehavioral development in mouse offspring. This study is the basis for investigating diseases associated with neurobehavioral development of adult offspring of pregnant shift-working women. Abstract: Most organisms on Earth have a biological clock, and their physiological processes are regulated by a 1-day cycle. In modern society, several factors can disturb these biological clocks in humans; in particular, individuals working in shifts are exposed to stark environmental changes that interfere with their biological clock. They have a high risk of various diseases. However, there are scarce experimental approaches to address the reproductive and health consequences of shift work in the offspring of exposed individuals. In this study, considering the fact that shift workers usually have their meals during their adjusted working time, we aimed to examine the effects of a 12-h shift with usual mealtime as a plausible night work model on the neurobehavioral development of adult mouse offspring. In these offspring, early exposure to this mealtime shift differentially affected circadian rhythmic variables and total locomotor activity depending on the timing and duration of restrictive feeding. Moreover, neurobehavioral alterations such as declined short-term memory and depressive-like behavior were observed in adulthood. These results have implications for the health concerns of shift-working women and their children.

Mealtime shift delays conception in mice.

The physiological processes of organisms in this rotating planet can adjust according to the time of day via built-in circadian clocks. However, more people are having different shift works, which can increase the risk of pathological conditions including altered reproductive function. Thus, circadian rhythm disturbance has become prevalent in the modern society. Specifically, epidemiological evidence has shown that shift-working women are at high risk of spontaneous abortions, irregular menstrual cycles, and low-birth-weight babies. The current study aimed to investigate the effects of circadian rhythm disturbances on the reproductive function of mice caused by dietary time shift, which is common among night-shift workers. According to the schedule of restricted feeding, the mice were classified into the free feeding, daytime feeding, and night feeding groups. The fertility indices of each group were then evaluated. Activity monitoring was performed to determine whether pregnancy delay might be attributed to mealtime shift. Moreover, the estrous cycle of female mice and the reproductive phenotype of male mice were investigated. Results showed that a 12-h mealtime shift significantly delayed successful conception, which could be attributed to a disrupted estrous cycle, in adult female mice.

Polydeoxyribonucleotide Ameliorates Lipopolysaccharide-Induced Lung Injury by Inhibiting Apoptotic Cell Death in Rats.

Lung injury is characterized by diffuse lung inflammation, alveolar-capillary destruction, and alveolar flooding, resulting in respiratory failure. Polydexyribonucleotide (PDRN) has an anti-inflammatory effect, decreasing inflammatory cytokines, and suppressing apoptosis. Thus, we investigated its efficacy in the treatment of lung injury, which was induced in rats using lipopolysaccharide (LPS). Rats were randomly divided into three groups according to sacrifice time, and each group split into control, lung injury-induced, and lung injury-induced + PDRN-treated groups. Rats were sacrificed 24 h and 72 h after PDRN administration, according to each group. Lung injury was induced by intratracheal instillation of LPS (5 mg/kg) in 0.2 mL saline. Rats in PDRN-treated groups received a single intraperitoneal injection of 0.3 mL distilled water including PDRN (8 mg/kg), 1 h after lung injury induction. Percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive, cleaved caspase-3-, -8-, and -9-positive cells, the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2), and expressions of inflammatory cytokines (tumor necrosis factor-α, interleukin-6) were decreased by PDRN treatment in the LPS-induced lung injury rats. Therefore, treatment with PDRN reduced lung injury score. This anti-apoptotic effect of PDRN can be ascribed to the enhancing effect of PDRN on adenosine A2A receptor expression. Based on these results, PDRN might be considered as a new therapeutic agent for the treatment of lung injury.

Treadmill exercise in obese maternal rats during pregnancy improves spatial memory through activation of phosphatidylinositol 3-kinase pathway in the hippocampus of rat pups.

Maternal nutrition is necessary for the growth of the fetus, and excessive intake of nutrients interferes with brain development in offspring. In the current study, the effect of treadmill running during pregnancy in obese maternal rats on spatial learning memory and spatial working memory in rat pups was investigated. Phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and extracellular signal-regulated kinase 1 and 2 (ERK1/2) was also identified in rat pups. Female rats were divided into the normal diet group and the high-fat diet group for 7 weeks, including pregnancy and lactation. Maternal treadmill running was performed for 4 weeks. The born rat pups were classified into a control group, a treadmill exercise group, a high-fat diet group, a high-fat diet and treadmill exercise group according to the status of maternal rats. Radial 8-arm maze task for spatial learning memory and Morris water maze task for spatial working memory were done. Western blot analysis was conducted to determine the expressions of PI3K, Akt, ERK1/2. In the current results, maternal treadmill running during pregnancy improved spatial learning memory and spatial working memory in rat pups born to obese maternal rats. This improving effect of memory was due to the enhanced phosphorylation of PI3K, Akt, and ERK1/2 by treadmill running.

Treadmill exercise in obese maternal rats during pregnancy improves short-term memory through neurogenesis in the hippocampus of rat pups.

Maternal obesity is known to increase the likelihood of offspring becoming obese, high blood pressure, and other metabolic disorders. After inducing obesity, the effect of treadmill exercise in maternal rats during pregnancy on short-term memory was investigated in relation to neurogenesis in rat pups. Short-term memory was declined in rat pups born to obese maternal rats, and treadmill running during pregnancy alleviated short-term memory impairment in rat pups born to obese maternal rats. The number of doublecortin (DCX)-positive and 5-bro-mo-2'-deoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus was decreased in rat pups born to obese maternal rats. Treadmill running during pregnancy increased the number of DCX-positive and BrdU-positive cells in rat pups born to obese maternal rats. Expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) in the hippocampus was decreased in the rat pups born to obese maternal rats. Treadmill running during pregnancy increased the expressions of BDNF and TrkB in rat pups born to obese maternal rats. Enhancing effect of short-term memory by treadmill exercise may be due to increased neurogenesis through activation of the BDNF-TrkB signaling pathway by treadmill exercise.

Combination of treadmill exercise with bone marrow stromal cells transplantation activates protein synthesis-related molecules in soleus muscle of the spinal cord injured rats.

The present study investigated whether treadmill exercise with bone marrow stromal cells (BMSCs) transplantation increase expression level of protein synthesis-related molecules in the soleus muscle after spinal cord injury (SCI). The spinal cord contusion injury was performed at the T9-10 level using the impactor (10 g×25 mm). BMSCs were cultured from femur and tibia of 4-week-old rats and then transplanted directly into the lesion 1-week post injury. The rats in exercise group were walking on treadmill device for 6 days per a week during 6 weeks. Prepared soleus muscles were used for examining mechanisms of protein synthesis after SCI. Myostatin induction level was increased by SCI, but BMSCs engrafting after SCI decreased compared to SCI group. Combination of treadmill exercise with BMSCs showed more potent decrement on myostatin expression. Protein kinase B (Akt) and mammalian target of rapamycin (mTOR) levels were significantly increased in SCI and BMSCs transplantation group compared to SCI group. Combination of treadmill exercise with BMSCs further facilitated expression levels of Akt and mTOR. Insulin-like growth factor-I (IGF-I) and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) induction levels were more increased in SCI and BMSC transplantation group compared to SCI group. Combination of treadmill exercise with BMSCs further increased expression levels of IGF-I and p-CREB, although statistical significance was not appeared. Combining treadmill exercise with BMSCs transplantation might accelerate protein synthesis and hypertrophy in the soleus muscle after SCI through activation of IGF-I/mTOR signaling pathway.

Treadmill Exercise Alleviates Circadian Rhythm Disruption-Induced Memory Deficits by Activation of Glucocorticoid Receptor and Brain-Derived Neurotrophic Factor-Dependent Pathway.

PURPOSE: Circadian rhythm affects learning process, memory consolidation, and long-term memory. In this study, the alleviating effect of exercise on circadian rhythm disruption-induced memory deficits was investigated. METHODS: BMAL1 knockdown transgenic mice (BMAL1 TG) were used as the BMAL1-TG group and the BMAL1-TG with treadmill exercise group. Female C57BL/6J mice of the same age were used as the wildtype group and the wildtype with treadmill exercise group. The mice in the treadmill exercise groups performed running on a motorized treadmill under the dark-dark conditions for 8 weeks. Short-term memory, nonspatial object memory, and spatial learning memory were determined using stepdown avoidance test, novel object-recognition test, and radial 8-arm maze test. Immunohistochemistry for doublecortin and 5-bromo-2'-deoxyuridine was conducted for the determination of hippocampal neurogenesis. Using the western blot analysis, we determined the expressions of glucocorticoid receptor (GR) and factors related to the neurogenesis and memory consolidation, such as brain-derived neurotrophic factor, tyrosine kinase B, p44/42 mitogen-activated protein kinase, cyclic AMP-responsive element binding protein, phosphatidylinositol 3-kinase, protein kinas B, protein kinase C alpha, early-growth-response gene 1. RESULTS: Circadian rhythm disruption impaired memory function through inhibiting the expressions of GR and the factors related to neurogenesis and memory consolidation. Treadmill exercise improved memory function via enhancing the expressions of GR and above-mentioned factors. CONCLUSION: Treadmill exercise acts as the zeitgeber that improves memory function under the circadian rhythm disrupted conditions.

Treadmill exercise with bone marrow stromal cells transplantation facilitates neuroprotective effect through BDNF-ERK1/2 pathway in spinal cord injury rats.

Transplantation of bone marrow stromal cells (BMSCs) has been known as one of the effective therapeutic methods for functional recovery of spinal cord injury (SCI). Treadmill exercise also facilitates the functional recovery of SCI. Previously, we reported that combination of BMSCs transplantation with treadmill exercise potentiated the locomotor function in SCI rats. In the present study, we investigated whether recovery effect of BMSCs transplantation or treadmill exercise appears through the brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinases 1/2 (ERK1/2) pathway. The spinal cord contusion injury was performed at the T9-T10 level using the impactor. Cultured BMSCs were transplanted directly into the lesion 1 week after SCI. Treadmill exercise was performed 6 days per a week for 6 weeks. Western blot for Bax, Bcl-2, BDNF, tyrosine kinase B (TrkB), and phosphorylated ERK1/2 (p-ERK1/2), phosphorylated JNK was performed. In the present results, combination of BMSCs transplantation with tread-mill exercise potently decreased Bax expression, potently increased Bcl-2 expression, and potently enhanced BDNF and TrkB expressions in the injured spinal cord. Combination of BMSCs transplantation with treadmill exercise further facilitated p-ERK1/2 and p-c-Jun expression levels. The present findings demonstrated the synergistic effect of treadmill exercise on neuroregenerative effect of BMSCs transplantation appeared through the activation of BDNF-ERK1/2 pathway in SCI.

Treadmill exercise improves memory function by inhibiting hippocampal apoptosis in pilocarpine-induced epileptic rats.

Epilepsy is characterized by recurrent seizures and loss of neurons with abnormal rhythmic firing in the brains. In the present study, we investigated the effect of treadmill exercise on memory function in relation with cell proliferation and apoptosis in the hippocampus using pilocarpine-induced seizure rats. Epilepsy was initiated by intraperitoneal injection of pilocarpine hydrochloride. The rats in the exercise group were forced to run on a motorized treadmill for 30 min once a day for 2 weeks. In the present results, treadmill exercise alleviated short-term and spatial learning memory impairments in the epileptic rats. Treadmill exercise suppressed neuronal degeneration and enhanced neuronal maturation in the epileptic rats. Treadmill exercise suppressed cell proliferation and apoptosis in the epileptic rats. Treadmill exercise alleviated pilocarpine-induced memory impairments and suppressed neuronal loss in the hippocampus through down-regulation of apoptosis. These findings offer a possibility that treadmill exercise may provide a preventive or therapeutic value to the epilepsy-induced learning and memory impairments.

Combination therapy with polydeoxyribonucleotide and proton pump inhibitor enhances therapeutic effectiveness for gastric ulcer in rats.

AIMS: The main action of proton pump inhibitors (PPIs) is to inhibit gastric acid secretion, and PPIs are widely used to treat gastric ulcer (GU). However, if the action of promoting gastric mucosal regeneration is added, the effectiveness of GU treatment can be enhanced. Thus, in order to improve the therapeutic effect on GU, we tried to develop combination therapy promoting regeneration in injured tissue besides suppressing gastric acid secretion. MAIN METHODS: Polydeoxyribonucleotide (PDRN) was selected to evaluate tissue regeneration, and pantoprazole was chosen as one of the PPIs. GU was induced by oral administration of indomethacin once a day for 7 days. Rats in drug-administered groups were intraperitoneally injected with 100 µL normal saline, containing each drug at the indicated concentration, once a day for 14 days after inducing GU. KEY FINDINGS: PDRN and PPI combination therapy potently improved tissue regeneration and inhibited production of pro-inflammatory cytokines. PDRN treatment with or without PPI increased the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) and the ratio of phosphorylated cAMP response element-binding protein (p-CREB) to cAMP response element-binding protein (CREB). PDRN treatment with or without PPI also increased the expressions of vascular endothelial growth factor (VEGF) and adenosine A2A receptor. SIGNIFICANCE: PDRN and PPI combination therapy showed more potent therapeutic effect on GU compared to the PDRN monotherapy or PPI monotherapy. The excellent therapeutic effect of PDRN and PPI combination therapy on GU appeared by promoting regeneration of damaged tissue as well as inhibiting gastric acid secretion.

Treadmill exercise with bone marrow stromal cells transplantation potentiates recovery of locomotor function after spinal cord injury in rats.

Transplantation of bone marrow stromal cells (BMSCs) is regarded as a promising candidate for the spinal cord injury (SCI). In the present study, we investigated whether treadmill exercise potentiate the effect of BM-SCs transplantation on the functional recovery in the SCI rats. The spinal cord contusion injury applied at the T9-T10 level using the impactor. Cultured BMSCs were transplanted into the lesion at 1 week after SCI induction. Treadmill exercise was conducted for 6 weeks. Basso-Beattie-Bresnahan (BBB) scale for locomotor function was determined. Sprouting axons in the lesion cavity were detected by immunofluorescence staining for neurofilament-200. Brain-derived neurotrophic factor (BDNF) and synapsin-I expressions were analyzed using western blotting. BMSCs transplantation improved BBB score and increased expressions of neurofilament-200, BDNF, and synapsin-I in the SCI rats. Treadmill exercise potentiated the improving effect of BMSCs transplantation on BBB score in the SCI rats. This potentiating effect of treadmill exercise could be ascribed to the enhancement of BDNF expression in the SCI rats.

Treadmill exercise ameliorates depressive symptoms through increasing serotonin expression in postpartum depression rats.

Postpartum depression (PPD) is defined as the depressive symptoms that occur from the moment of delivery until 12 months after delivery. PPD symptoms are closely associated with reduced activity of the serotonergic system. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step of 5-HT biosynthesis in the serotonergic neurons. Exercise exerts anti-depressive effect on depression patients as well as on animal models of depression. In the present study, the effect of treadmill exercise on PPD was investigated using rats. For this study, open field test for activity and forced swimming test for depressive symptoms, and immunohistochemistry for 5-HT and TPH were conducted. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 2 weeks. Activity in the open field test was decreased in the postpartum rats, however, performing treadmill running increased activity in the postpartum rats. The climbing time was decreased and the immobility time was increased in the postpartum rats. Treadmill exercise increased climbing time and suppressed immobility time in the postpartum rats. 5-HT and TPH expressions in the dorsal raphe were suppressed in the postpartum rats, and treadmill exercise enhanced 5-HT and TPH expressions in the postpartum rats. Treadmill exercise ameliorated the PPD very effectively by enhancing serotonin level.

Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats.

Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats.

Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups.

Autism is a neurodevelopmental disorder and this disorder shows impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive patterns of behaviors and interests. The effect of music on short-term memory in the view of cell proliferation in the hippocampus was evaluated using valproic acid-induced autistic rat pups. Animal model of autism was made by subcutaneous injection of 400-mg/kg valproic acid into the rat pups on the postnatal day 14. The rat pups in the music-applied groups were exposed to the 65-dB comfortable classic music for 1 hr once a day, starting postnatal day 15 and continued until postnatal day 28. In the present results, short-term memory was deteriorated by autism induction. The numbers of 5-bromo-2'-deoxyridine (BrdU)-positive, Ki-67-positive, and doublecortin (DCX)-positive cells in the hippocampal dentate gyrus were decreased by autism induction. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expressions in the hippocampus were also suppressed in the autistic rat pups. Music application alleviated short-term memory deficits with enhancing the numbers of BrdU-positive, Ki-67-positive, and DCX-positive cells in the autistic rat pups. Music application also enhanced BDNF and TrkB expressions in the autistic rat pups. The present study show that application of music enhanced hippocampal cell proliferation and alleviated short-term memory impairment through stimulating BDNF-TrkB signaling in the autistic rat pups. Music can be suggested as the therapeutic strategy to overcome the autism-induced memory deficits.

Treadmill exercise ameliorates motor dysfunction through inhibition of Purkinje cell loss in cerebellum of valproic acid-induced autistic rats.

Autism is a complex developmental disorder with impairments in social interaction, communication, repetitive behavior and motor skills. Exercise enhances cognitive function, ameliorates motor dysfunction, and provides protective profits against neurodegeneration. In the present study, we evaluated the effect of treadmill exercise on the motor coordination and Purkinje cell loss in relation with reactive astrocytes and microglial activation in the cerebellum using valproic acid (VPA)-induced autism rat model. On the 12th day of pregnancy, the pregnant rats in the VPA-exposed group received intraperitoneal injections of 600-mg/kg VPA. After birth, the rat pups were divided into four groups: the control group, the exercise group, the VPA-treated group, the VPA-treated and exercise group. The rat pups in the exercise groups were forced to run on a treadmill for 30 min once a day, 5 times a week for 4 weeks. In the present results, motor balance and coordination was disturbed by induction of autism, in contrast, treadmill exercise alleviated motor dysfunction in the autistic rats. Purkinje cell loss, reactive astrocytes, and microglial activation were occurred by induction of autism, in contrast, treadmill exercise enhanced survival rate of Purkinje neurons through inhibition of reactive astrocytes and microglia in the autistic rats. The present study showed that exercise may provide a potential therapeutic strategy for the alleviation of motor dysfunction in autistic patients.

Treadmill exercise ameliorates intracerebral hemorrhage-induced depression in rats.

Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with high mortality rate. Depression is one of the most common complications of ICH. In the present study, the effects of treadmill exercise on ICH-induced depressive symptoms in relation with apoptosis were investigated using rats. ICH rat model was induced by injection of collagenase into the hippocampus using stereotaxic instrument. Open field test for activity and forced swimming test for depressive symptoms were conducted. Apoptosis in the hippocampus was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3, and western blot for Bcl-2 and Bax. Western blot analysis for 5-hydroxy-tryptamine (5-HT, serotonin) and tryptophan hydroxylase (TPH) in the dorsal raphe was also conducted for biomarkers of depression. In the present results, immobility time was increased and climbing time was decreased by induction of ICH and treadmill exercise inhibited immobility time and increased climbing time in ICH rats. DNA fragmentation and caspase-3 expression in the hippocampal dentate gyrus were enhanced by induction of ICH and treadmill exercise suppressed ICH-induced DNA fragmentation and caspase-3 expression. Bax expression in the hippocampus was increased by induction of ICH and treadmill exercise inhibited Bax expression in the ICH rats. Expressions of 5-HT and TPH in the dorsal raphe were decreased by induction of ICH and treadmill exercise increased expressions of 5-HT and TPH in the ICH rats. In the present study, treadmill exercise ameliorated depressive symptoms through inhibiting apoptosis.

Treadmill Exercise Improves Memory Function Depending on Circadian Rhythm Changes in Mice.

PURPOSE: Exercise enhances memory function by increasing neurogenesis in the hippocampus, and circadian rhythms modulate synaptic plasticity in the hippocampus. The circadian rhythm-dependent effects of treadmill exercise on memory function in relation with neurogenesis were investigated using mice. METHODS: The step-down avoidance test was used to evaluate short-term memory, the 8-arm maze test was used to test spatial learning ability, and 5-bromo-2'-deoxyuridine immunofluorescence was used to assess neurogenesis. Western blotting was also performed to assess levels of synaptic plasticity-associated proteins, such as brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphorylated cAMP response element-binding protein, early growth response protein 1, postsynaptic density protein 95, and growth-associated protein 43. The mice in the treadmill exercise at zeitgeber 1 group started exercising 1 hour after sunrise, the mice in the treadmill exercise at zeitgeber 6 group started exercising 6 hours after sunrise, and the mice in the treadmill exercise at zeitgeber 13 group started exercising 1 hour after sunset. The mice in the exercise groups were forced to run on a motorized treadmill for 30 minutes once a day for 7 weeks. RESULTS: Treadmill exercise improved short-term memory and spatial learning ability, and increased hippocampal neurogenesis and the expression of synaptic plasticity-associated proteins. These effects of treadmill exercise were stronger in mice that exercised during the day or in the evening than in mice that exercised at dawn. CONCLUSIONS: Treadmill exercise improved memory function by increasing neurogenesis and the expression of synaptic plasticity-associated proteins. These results suggest that the memory-enhancing effect of treadmill exercise may depend on circadian rhythm changes.

Neuroprotective Effects of Bone Marrow Stromal Cell Transplantation in Combination With Treadmill Exercise Following Traumatic Brain Injury.

PURPOSE: Traumatic brain injury (TBI) causes cognitive impairments, motor deficits, and neuropsychiatric/behavioral deficits problems. Transplantation of bone marrow stromal cells (BMSCs) facilitates functional recovery from brain insults. Treadmill exercise increases neurogenesis and inhibits apoptosis. In this study, we investigated the effects of BMSC transplantation in combination with treadmill exercise on memory function, by evaluating its effect on neurogenesis and apoptosis in the hippocampus following TBI. METHODS: TBI was induced using an electromagnetic-controlled cortical impact device. BMSCs were transplanted into both sides of traumatic scar region 1 week after TBI induction. One week after transplantation of BMSCs, the rats in the exercise groups were trained to run on a treadmill for 30 minutes once daily for 28 days. Step-down avoidance task and radial 8-arm maze test were conducted. Levels of 5-bromo-2ʹ-deoxyuridine and caspase-3 were evaluated using immunohistochemistry. Western blot was used to evaluate the expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), total-extracellular signal-regulated kinase 1 and 2 (t-ERK1/2), phosphorylated-ERK1/2 (p-ERK1/2), Bcl-2, and Bax. RESULTS: TBI deteriorated memory function, suppressed neurogenesis, and accelerated apoptosis in the hippocampus. Treadmill exercise and BMSC transplantation independently improved memory function by increasing neurogenesis with suppression of apoptosis through the BDNF-ERK pathway in the TBI-induced rats. Combination of BMSC transplantation with treadmill exercise showed additional enhancement of neurogenesis and suppression of apoptosis in the hippocampus. CONCLUSIONS: The present study shows that treadmill exercise may aid the therapeutic effect of BMSC transplantation on TBI in rats.

Effects of Combination Treatment of Alpha 1-Adrenergic Receptor Antagonists on Voiding Dysfunction: Study on Target Organs in Overactive Bladder Rats.

PURPOSE: Overactive bladder (OAB) causes urinary urgency, usually accompanied by frequency and nocturia. Alpha 1-adrenergic receptor (α1-AR) antagonists are known to improve lower urinary tract symptoms associated with OAB. The α1-AR antagonists constitute a variety of drugs according to the receptor subtype affinity. This study investigated the efficacy of tamsulosin, naftopidil, and a combination of the two on OAB rats. METHODS: The OAB rat model was induced by an intraperitoneal injection of cyclophosphamide for 14 days. The experimental groups were divided into 5 groups: control group, OAB-induction group, OAB-induction and tamsulosin monotherapy group, OAB-induction and naftopidil monotherapy group, and OAB-induction and tamsulosin-naftopidil combination therapy group. For the drug-treated groups, each drug was administrated for 14 days after the OAB induction. Cystometry for urodynamic evaluation and immunohistochemical stain for c-Fos and nerve growth factor (NGF) expressions in the central micturition centers were performed. RESULTS: Increased contraction pressure and time with enhanced c-Fos and NGF expressions in the central micturition centers were found in the OAB rats. Tamsulosin suppressed contraction pressure and time while inhibiting c-Fos and NGF expressions. Naftopidil showed no significant effect and combination therapy showed less of an effect on contraction pressure and time. Naftopidil and combination therapy exerted no significant effect on the c-Fos and NGF expressions. CONCLUSIONS: Tamsulosin showed the most prominent efficacy for the treatment of OAB compared to the naftopidil and combination. The combination of tamsulosin with naftopidil showed no synergistic effects on OAB; however, further studies of addon therapy might provide opportunities to find a new modality.

Effects of surgical and chemical castration on spatial learning ability in relation to cell proliferation and apoptosis in hippocampus.

PURPOSE: Chemical castration using luteinizing hormone-releasing hormone agonists and/or anti-androgens is an alternative to surgical castration. Goserelin and bicalutamide are representative drugs used for chemical castration. The effects of chemical castration on sexual functions are well documented; however, the possibility that chemical castration might induce undesirable effects on brain functions has been raised. We investigated the effects of chemical castration and surgical castration on spatial learning ability in relation to cell proliferation and apoptosis in hippocampus. METHODS: Bilateral orchiectomy was performed for surgical castration, and chemical castration was induced by treatment with goserelin or bicalutamide for 28 days. To find out the effects of goserelin and bicalutamide with those of orchiectomy on the spatial learning ability, radial eight-arm maze test was performed. To find out the effects of goserelin and bicalutamide with those of orchiectomy in relation to cell proliferation and apoptosis in the hippocampus, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, and immunohistochemistry for 5-bromo-2'-deoxyuridine, doublecortin, and caspase-3 were performed. Western blot for brain-derived neurotrophic factor, tyrosine kinase receptor B, Bax, and Bcl-2 in the hippocampus was also performed. RESULTS: Orchiectomy caused deterioration of spatial learning ability with suppression of cell proliferation and enhancement of apoptosis in the hippocampus. However, treatment with goserelin and bicalutamide had no effect on spatial learning ability. Cell proliferation and apoptosis were not altered by treatment with goserelin and bicalutamide either. CONCLUSIONS: Surgical castration causes deterioration of spatial learning ability, while chemical castration does not impair spatial learning ability. We should find out further mechanisms affect to the relationship between androgen level and neurogenesis and neuronal apoptosis.