The low and high doses administration of lutein improves memory and synaptic plasticity impairment through different mechanisms in a rat model of vascular dementia.

BACKGROUND AND AIM: Vascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats. EXPERIMENTAL PROCEDURE: The rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level. RESULT: Treatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group. CONCLUSIONS: Treatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.

The combination treatment of hypothermia and intranasal insulin ameliorates the structural and functional changes in a rat model of traumatic brain injury.

The present study aimed to investigate the combination effects of hypothermia (HT) and intranasal insulin (INS) on structural changes of the hippocampus and cognitive impairments in the traumatic brain injury (TBI) rat model. The rats were divided randomly into the following five groups (n = 10): Sham, TBI, TBI with HT treatment for 3 h (TBI + HT), TBI with INS (ten microliters of insulin) treatment daily for 7 days (TBI + INS), and TBI with combining HT and INS (TBI + HT + INS). At the end of the 7th day, the open field and the Morris water maze tests were done for evaluation of anxiety-like behavior and memory performance. Then, after sacrificing, the brain was removed for stereological study. TBI led to an increase in the total volume of hippocampal subfields CA1 and DG and a decrease in the total number of neurons and non-neuronal cells in both sub-regions, which was associated with anxiety-like behavior and memory impairment. Although, the combination of HT and INS prevented the increased hippocampal volume and cell loss and improved behavioral performances in the TBI group. Our study suggests that the combined treatment of HT and INS could prevent increased hippocampal volume and cell loss in CA1 and DG sub-regions and consequently improve anxiety-like behaviors and memory impairment following TBI.

The combination treatment of methylprednisolone and growth factor-rich serum ameliorates the structural and functional changes after spinal cord injury in rat.

STUDY DESIGN: Preclinical pharmacology. OBJECTIVES: Our study aims to evaluate the combined effect of Methylprednisolone (MP) and growth factor-rich serum (GFRS) on structural and functional recovery in rats following spinal cord injury (SCI). SETTING: Shiraz University of Medical Sciences, Shiraz, Iran METHODS: Male Sprague-Dawley rats were randomly assigned to five groups: sham group (laminectomy); SCI group (the spinal cord clip compression model); SCI-MP group (30 mg/kg MP was administrated intraperitoneally (IP) immediately after SCI); SCI-GFRS group (GFRS (200 µl, IP) was administrated for six consecutive days); and SCI-MP + GFRS group (the rats received MP (30 mg/kg, IP) immediately after SCI, and GFRS (200 µl, IP) for six consecutive days). Motor function was assessed weekly using the Basso, Beattie, and Bresnahan (BBB) scale. After 4 weeks, we conducted the rotarod test, then removed and prepared the spinal cords (including the epicenter of injury) for stereological and histological estimation, and biochemical assays. RESULTS: The results showed that MP and GFRS combining treatment enhanced functional recovery, which was associated with a decrement in lesion volume, increased spared white and gray matter volume, reduced neuronal loss, as well as decreased necrosis and hemorrhage after SCI. Moreover, administration of MP and GFRS inhibited lipid peroxidation (malondialdehyde (MDA) content), and increased antioxidant enzymes including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) after rat SCI. CONCLUSIONS: We suggests that the combination treatment of MP and GFRS may ameliorate the structure and functional changes following SCI by reducing oxidative stress, and increasing the level of antioxidants enzymes.

The Effect of Mesenchymal Stem Cells Derived-Conditioned Media in Combination with Oral Anti-Androgenic Drugs on Male Pattern Baldness: An Animal Study.

OBJECTIVE: Androgenetic alopecia (AGA) is a prevalent form of hair loss, mainly caused by follicular sensitivity to androgens. Despite developing different anti-androgen treatment options, the success rate of these treatments has been limited. Using animal models, this study evaluated the therapeutic effects of umbilical cord (UC) stem cell conditioned media (CM) combined with oral anti-androgens for hair regeneration. MATERIALS AND METHODS: In this experimental study, Poloxamer 407 (P407) was used as a drug carrier for subcutaneous testosterone injection. AGA models were treated with oral finasteride, oral flutamide, and CM injections. Samples were thoroughly evaluated and compared using histological, stereological, and molecular analyses. RESULTS: Injecting CM-loaded hydrogel alone or combined with oral intake of anti-androgens improved hair regeneration. These treatments could promote hair growth by inducing hair follicles in the anagen stage and shortening the telogen and catagen phases. Furthermore, the combination treatment led to an upregulation of hair induction gene expression with a downregulation of inflammation genes. CONCLUSION: Through a reduction in inflammation, injection of CM-loaded hydrogel alone or combined with oral intake of anti-androgens induces the hair cell cycle with regeneration in damaged follicles. Hence, this could be a promising therapeutic method for AGA patients.

Sleep deprivation induces structural changes in the adult rat testis: The protective effects of olive oil.

OBJECTIVE: Sleep deprivation (SD) is a common problem in today's stressful lifestyle and have physiological consequences, including reproductive dysfunction and infertility. As an antioxidant, olive oil may be effective in reducing testicular and spermatological damage by decreasing the production of free radicals. METHODS: This study investigated the effects of olive oil on sperm quality and testicular structure using stereological methods to assess rats with SD. RESULTS: When comparing SD group to grid floor+distilled water (GR) group, we found that the sperm count and motility, as well as the percentage of slow progressive sperm was significantly lower in SD group (p<0.05), but the percentage of immotile sperm was higher (p<0.01). However, no improvement was observed in sperm count or motility after concomitant treatment of SD group with olive oil. Stereological examinations revealed no significant change in the total volumes of the seminiferous tubules, interstitial tissue, and germinal epithelium in the study groups. Conversely, the total number of testicular cell types was significantly lower in SD group than in GR group. Although the total number of Sertoli and Leydig cells was significantly higher in the SD+olive oil group than in the untreated SD group, no significant difference in the total number of other testicular cell types was observed between the two groups. CONCLUSION: SD potentially induced structural changes in testis that affected sperm count and motility. However, olive oil only improved the total number of Sertoli and Leydig cells in the animals with SD and did not improve sperm count and motility.

The impact of anesthetic drugs on hemodynamic parameters and neurological outcomes following temporal middle cerebral artery occlusion in rats.

The induction of ischemic stroke in the experimental model requires general anesthesia. One of the factors that can be effective in the size of ischemic brain lesions and neurological outcomes is the type of anesthesia. So, the current study was designed to compare the impacts of the most important and widely used anesthetics including halothane, isoflurane, and chloral hydrate on the transient middle cerebral artery occlusion (MCAO) outcomes. Adult Male Sprague-Dawley rats were randomly divided into three groups as follows: (1) MCAO + halothane group, (2) MCAO + isoflurane group, and (3) MCAO + chloral hydrate group. After 24 h, the mortality rate, infarct size, tissue swelling, neurological function, hemodynamic, and arterial blood gas parameters were assessed. Our finding showed that 60 min MCAO rats anesthetized with chloral hydrate significantly increased mortality rate, infarct size, tissue swelling, and neurological deficits compared with halothane and isoflurane anesthetics after 24 h of MCAO. Also, chloral hydrate caused a significant decrease in mean arterial pressure and arterial pO2 compared to halothane and isoflurane anesthetics. On the basis of the current data, we concluded that chloral hydrate increased cerebral infarct volume and neurological outcomes and reduced hemodynamic and metabolic parameters compared with halothane and isoflurane-anesthetized rats temporal MCAO.

Resveratrol ameliorates bisphenol A-induced testicular toxicity in adult male rats: a stereological and functional study.

BACKGROUND: Bisphenol A (BPA) is one of the most widely used synthetic chemicals worldwide. BPA as an endocrine disruptor affects the reproductive systems through estrogenic and antiandrogenic proprieties. Resveratrol (RES) as a natural polyphenol and potent antioxidant exhibits protective effects against reproductive toxicity by inhibiting of oxidative stress. 48 male rats were divided into eight groups (n=6), including CONTROL, OLIVE OIL (0.5 ml/ day), Carboxy methylcellulose (CMC) (1 ml of 10 g/l), RES (100mg/kg/day), low dose of BPA (25 mg/kg/day), high dose of BPA (50 mg/kg/day), low dose of BPA + RES, and high dose of BPA + RES. All treatments were done orally per day for 56 days. At the end of the 8th week, blood samples were collected for hormone assays. Then, the sperm parameters were analyzed, and the left testis was removed for stereological study. RESULTS: We showed a significant decrease in sperm parameters in the low and high doses of BPA groups compared to control groups (P<0.05). The volume of testicular components as well as the diameter and length of seminiferous tubules significantly reduced (11-64 %), and the total number of the testicular cell types decreased (34-67 %) on average in the low and high doses of BPA groups. Moreover, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone hormones concentration showed a significant reduction in both doses of BPA groups (P<0.01). Nonetheless, treatment with RES could ameliorate all the above-mentioned changes in the low and high doses of BPA groups (P<0.05). CONCLUSIONS: RES could prevent BPA-induced testicular structural changes and sperm quality via improving gonadotropin hormones and testosterone levels.

RèSUMè: CONTEXTE: Le bisphénol A (BPA) est l'un des produits chimiques synthétiques les plus utilisés dans le monde. Le BPA en tant que perturbateur endocrinien affecte le système reproducteur par le biais de ses propriétés œstrogéniques et anti-androgènes. Le resvératrol (RES), en tant que polyphénol naturel et puissant antioxydant, présente des effets protecteurs contre la toxicité sur la reproduction en inhibant le stress oxydatif. Quarante-huit rats mâles ont été divisés en huit groupes (n = 6), comprenant les groupes TÉMOIN, HUILE D'OLIVE (0,5 ml/jour), méthylcellulose Carboxyle (MCC) (1 ml de 10 g/L), RES (100 mg/kg/ jour), faible dose de 25 de BPA (25 mg/kg/jour), dose élevée de BPA (50 mg/kg/jour), faible dose de BPA + RES et dose élevée de BPA + RES. Tous les traitements ont été effectués quotidiennement par voie orale pendant 56 jours. À la fin de la 8ème semaine, des échantillons de sang ont été prélevés pour dosages hormonaux. Ensuite, les paramètres du sperme ont été analysés et le testicule gauche a été retiré pour une étude stéréologique. RéSULTATS: Nous avons montré une diminution significative des paramètres spermatiques dans les groupes traités par doses faibles et doses élevées de BPA par rapport aux groupe témoin (P<0,05). Le volume des composants testiculaires ainsi que le diamètre et la longueur des tubules séminifères ont été considérablement réduits (11-64 %) ; le nombre total des types de cellules testiculaires a diminué (34-67 %) en moyenne dans les groupes traités par doses faibles et doses élevées de BPA. De plus, la concentration sérique d'hormone folliculostimulante (FSH), lutéinisante (LH) et de testostérone a montré une réduction significative dans les groupes traités quelle que soit la dose de BPA (P<0,01). Néanmoins, le traitement par RES pourrait améliorer tous les changements mentionnés ci-dessus dans les groupes traités par doses faibles et élevées de BPA (P<0,05). CONCLUSIONS: Le RES pourrait avoir un effet positif sur les changements structurels testiculaires induits par le BPA, ainsi que la qualité du sperme, en améliorant les taux sériques d'hormones gonadotrophines et de testostérone. MOTS-CLéS: Bisphénol A Resvératrol Toxicité testiculaire Paramètres du Sperme Stéréologie.

The Comparative Effects of Dexamethasone, Nanocurcumin, and Coenzyme Q10 Against Lumbar Laminectomy-Induced Epidural Fibrosis in a Rat Model.

BACKGROUND: One of the major problems in neurosurgical procedures is fibrosis formation. Therefore, the prevention of fibrosis is an important issue in spinal cord injury that needs to be addressed. No approved therapy has yet been found, and epidural fibrosis (EF) is a huge treatment challenge. In this regard, new drugs that can effectively prevent EF are still being considered. Hence, this study aimed to investigate the effects of dexamethasone (DEX), nanocurcumin (Nano-CUR), and coenzyme Q10 (CoQ10) on the prevention of EF in a rat laminectomy model. METHODS: Thirty-five Sprague-Dawley male rats were randomly divided into 5 groups: sham group, laminectomy group, laminectomy + DEX group, in which 0.5 ml DEX (8 mg/ml) was applied locally on the laminectomy area, laminectomy + Nano-CUR group, in which 100 mg/kg Nano-CUR was administered intraperitoneally once a day for 7 days, and laminectomy + CoQ10 group, in which 30 mg/kg CoQ10 was administered once daily intraperitoneally for 7 days. After 4 weeks, the vertebral columns were removed from L1 and L3 and prepared for histopathological assays. RESULTS: The local administration of DEX could not improve the histological parameters, and EF was induced by laminectomy after 4 weeks. On the other hand, Nano-CUR could ameliorate EF at the laminectomy site compared to the laminectomy group, but the difference was not statistically significant. CoQ10 significantly reduced EF (P < 0.05), collagen density (P < 0.01), and inflammation in the arachnoid layer (P < 0.01). CONCLUSIONS: Our findings showed that Nano-CUR and CoQ10 had the potential to be used for treatment of EF.

Simultaneous Association of Variations in the Origin and Diameter of the Left Vertebral Artery in a Patient with a C1 Lateral Mass Tumor.

The anomalous origin of a hypoplastic Left Vertebral Artery (LVA) from the aortic arch is a rare anatomic variant. This study discusses the case of a patient with a C1 lateral mass tumor that surrounded a dominant Right Vertebral Artery (RVA) according to preoperative computed tomography angiography, with a hypoplastic LVA originating from the aortic arch. Surgery was performed, and the patient recovered uneventfully. To date, no study has reported the simultaneous association of two variations (origin and diameter) in the LVA. A deep understanding of abnormalities in the diameter and origin of LVA is a must for neurosurgeons as well as for thoracic and vascular surgeons to conduct surgical procedures.

A stereological study reveals nanoscale-alumina induces cognitive dysfunction in mice related to hippocampal structural changes.

Aluminum (Al) is known to induce neurotoxicity in both humans and rodents. Recent evidence has indicated that the toxicity of Al Oxide (Al2O3) nanoparticles (Al-NP), one of the most abundantly used engineered nanoparticles, is far greater than that of Al itself. To date, however, no information is available regarding the effect of Al-NP on the stereological parameters of hippocampus. In particular, no stereological studies have evaluated the effect of Al-NP on hippocampal CA1, dentate gyrus volume, and number of pyramidal and granular cells. Thus, the present study aimed to take a multidimensional approach to assess the concomitant cognitive, stereological, and apoptotic changes induced by a five-day Al-NP ingestion (10 mg/kg/day) in mice. The results demonstrated that the five-day Al-NP ingestion elicited a reduced preference to explore a novel object in the novel object recognition test (a hippocampal-dependent task). Perhaps contributing to this memory deficit, Al-NP induced additional alterations in the hippocampus of male NMRI mice in terms of (1) hippocampal volume (decreased the volume of the whole hippocampus, CA1, and dentate gyrus regions), (2) cell number (decreased the number of CA1 pyramidal neurons and dentate gyrus granular cells), and (3) increased cleaved caspase-3 in the whole hippocampus. These results provided new mechanistic insight to understand the impairing effect of AL-NP on the hippocampal function and structure.

Neuroprotective effects of sodium valproate on hippocampal cell and volume, and cognitive function in a rat model of focal cerebral ischemia.

Valproate (VPA) as a histone deacetylase (HDAC) inhibitor has shown neuroprotective effects in neurodegenerative diseases. This study evaluated whether VPA treatment ameliorated the synaptic plasticity dysfunction, hippocampal neuronal loss, and spatial memory deficits induced by cerebral ischemia in the middle cerebral artery occlusion (MCAO) model. Thirty-two male Sprague-Dawley rats were randomly divided into 4 groups control, sham, cerebral ischemia+vehicle (MCAO+V), and MCAO+VPA. The right common carotid artery was occluded for 1 hour. VPA (300 mg/kg) or vehicles were injected intraperitoneally on days 0,1,2 and 3 of the reperfusion. After 7 days of reperfusion the Morris water maze, passive avoidance, and open field tests were performed. Hippocampal synaptic plasticity in the CA1 area was recorded by field potential recording. We used the term neuronal Input-Output (I/O) function and paired-pulse ratio (PPR) to refer to basal synaptic transmission and presynaptic neurotransmitter release probability respectively. After that, the brains were removed for assaying stereological parameters of the CA1 neurons. Our results showed the VPA administration significantly reduced the total infarct volume, improved MCAO-induced spatial learning -memory, fear memory, and anxiety compared to the MCAO+V group. In addition, the field potential recording showed that VPA significantly ameliorated the impaired the long- term potentiation (LTP) induced by MCAO, without any effects on basal synaptic transmission and neurotransmitter release probability. Therefore, it seems that a decrease in total infarct volume and induction of long-term potentiation via postsynaptic mechanisms is responsible for improving MCAO-induced cognitive impairment.

Post-weaning exposure to Sunset Yellow FCF induces behavioral impairment and structural changes in the adult rat medial prefrontal cortex: Protective effects of Coenzyme Q10.

Sunset Yellow FCF (E110) is a water-soluble synthetic dye that has adverse neurobehavioral effects. Coenzyme Q10 (CoQ10) is known as a neuroprotective agent. The present study aimed to evaluate the effects of post-weaning exposure to Sunset Yellow FCF on behavioral and structural changes in the adult rat medial prefrontal cortex (mPFC) and the protective effects of CoQ10. The weanling rats were randomly divided into six groups: distilled water, CoQ10 (10 mg/kg/day), and low (2.5 mg/kg/day) and high (70 mg/kg/day) doses of Sunset Yellow FCF with or without CoQ10 consumption for 6 weeks. A battery of behavioral tests including open field and Morris water maze tests were done at the end of the sixth week, and then the animals' brains were removed for stereological methods. Our finding indicated that the high dose of Sunset Yellow FCF led to a reduced total volume of mPFC (15.16%), especially in the anterior cingulate cortex (ACC) region (21.96%), along with loss of neurons (32%) and glial cells (37%), which was associated with higher anxiety behavior and loss of spatial memory. However, CoQ10 prevented the neural loss and glial cells, improved anxiety-like behaviors, and memory impairment. On the other hand, the acceptable daily dose (low dose of Sunset Yellow FCF) did not show a discernible effect on the same parameters. This study showed that the CoQ10 can protect the alteration in mPFC structure and behavioral changes of the rats exposed to high dose of Sunset Yellow FCF.

The effects of copper sulfate on the structure and function of the rat cerebellum: A stereological and behavioral study.

Copper (Cu) is a vital trace element that acts as a cofactor of proteins and enzymes in many molecular pathways including the central nervous system. The accumulation or deficiency of copper could alter neuronal function and lead to neuronal degeneration and brain dysfunction. Intake of high levels of copper can also cause copper toxicosis that affects the brain structure and function. Despite clinical and experimental data indicating the association between abnormal copper homeostasis and brain dysfunction, the effects of copper on cerebellum have remained poorly understood. Hence, this study aimed to evaluate the effects of copper sulfate on the cerebellum via stereological and behavioral methods in rats. Male rats (Sprague-Dawley) were divided to three groups. The rats in the control group orally received distilled water, while those in the Cu groups received 1 mM (159 mg/L) or 8 mM (1272 mg/L) copper sulfate by oral gavage solved in distilled water daily for 4 weeks. Then, the rotarod performance test was recorded and the cerebellum was prepared for stereological assessments. The Cu-administered rats (1 and 8 mM) exhibited a significant reduction in the total volumes of the cerebellum structures. The total number of the cells in the cerebellar cortex and deep cerebellar nuclei were significantly decreased via Cu in a dose-dependent manner. Furthermore, the length of nerve fibers and the number of spines per nerve fiber decreased significantly in the Cu groups. These changes were correlated to the animals' motor performance impairment in the rotarod test. The findings suggested that copper toxicity induced motor performance impairments in the rats, which could be attributed to its deleterious effects on the cerebellum structure.

The Protective Effects of Coenzyme Q10 and Lisinopril Against Doxorubicin-Induced Cardiotoxicity in Rats: A Stereological and Electrocardiogram Study.

Doxorubicin (DOX) is used as an anticancer drug despite its several side effects, especially its irreversible impacts on cardiotoxicity. Coenzyme Q10 (Q10) as a powerful antioxidant and lisinopril (LIS) as an angiotensin-converting enzyme inhibitor seem to provide protection against DOX-induced cardiotoxicity. Therefore, this study aimed to assess the cardioprotective effects of Q10 and LIS against DOX-induced cardiotoxicity in rats. Adult male Sprague-Dawley rats were randomly assigned into the control, LIS, Q10, DOX, DOX + LIS, and DOX + Q10 groups. On day 21, ECG was recorded and the right ventricle was dissected for evaluation of catalase activity and malondialdehyde (MDA) concentration. Additionally, the left ventricle and the sinoatrial (SA) node were dissected to assess the stereological parameters. The results of ECG indicated bradycardia and increase in QRS duration and QT interval in the DOX group compared to the control group. Meanwhile, the total volumes of the left ventricle, myocytes, and microvessels and the number of cardiomyocyte nuclei decreased, whereas the total volume of the connective tissue and the mean volume of cardiomyocytes increased in the DOX group. On the other hand, the SA node and the connective tissue were enlarged, while the volume of the SA node nuclei was reduced in the DOX group. Besides, catalase activity was lower and MDA concentration was higher in the DOX-treated group. Q10 could recover most stereological parameters, catalase activity, and MDA concentration. LIS also prevented some stereological parameters and ECG changes and improved catalase activity and MDA concentration in the DOX group. The findings suggested that Q10 and LIS exerted cardioprotective effects against DOX-induced cardiac toxicity.

Treatment with edaravone improves the structure and functional changes in the hippocampus after chronic cerebral hypoperfusion in rat.

This study aimed to find out cellular and electrophysiological effects of the edaravone (EDR) administration following induction of vascular dementia (VaD) via bilateral-carotid vessel occlusion (2VO). The rats were randomly divided into control, sham, 2VO + V (vehicle), and 2VO + EDR groups. EDR was administered once a day from day 0-28 after surgery. The passive-avoidance, Morris water-maze, and open-field tests were used for evaluation of memory, locomotor, and anxiety. The field-potential recording was used for assessment of electrophysiological properties of the hippocampus; and after sacrificing, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels. The long-term potentiation (LTP), paired-pulse ratio (PPR), and input-output (I/O) curves were evaluated as indexes for long-term and short-term synaptic plasticity, and basal-synaptic transmission (BST), respectively. The 2VO led to increases in MDA level with considerable neuronal loss and decreases in the volume of the hippocampus, along with a reduction in the BST and LTP induction which was associated with a decrement in PPR and ultimate loss in memory with higher anxiety behavior. However, administration of EDR caused a decline in MDA and prevented the neural loss and volume of the hippocampus, rescued BST and LTP depression, improved memory and anxiety without any effects on PPR. Therefore, most likely through the improvement of MDA level, and the hippocampal cell number and volume, EDR leads to recovery of synaptic plasticity and behavioral performance. Because of the LTP rescue, without recovery of PPR, it is likely that the EDR improved LTP through the post-synaptic neurons.

The emerging role of FTY720 as a sphingosine 1-phosphate analog for the treatment of ischemic stroke: The cellular and molecular mechanisms.

Finding novel and effective drugs for the treatment of ischemic stroke is warranted because there is not a definitive treatment for this prevalent disease. Due to the relevance between the sphingosine 1-phosphate (S1P) receptor and several neurological diseases including ischemic stroke, it seems that fingolimod (FTY720), as an agonist of S1P receptor, can be a useful therapeutic strategy in these patients. FTY720 is the first oral drug approved by the US food and drug administration for the treatment of multiple sclerosis. Three important mechanisms for neuroprotective effects of FTY720 have been described. First, the functional antagonistic mechanism that is associated with lymphopenia and reduced lymphocytic inflammation. This effect results from the down-regulation and degradation of lymphocytes' S1P receptors, which inhibits lymph node lymphocytes from entering the bloodstream. Second, a functional agonistic activity that is mediated through direct effects via targeting S1P receptors on the membrane of various cells including neurons, microglia, oligodendrocytes, astrocytes, and endothelial cells of blood vessels in the central nervous system (CNS), and the third, receptor-independent mechanisms that are displayed by binding to specific cellular proteins that modulate intracellular signaling pathways or affect epigenetic transcriptions. Therefore, we review these mechanisms in more detail and describe the animal model and in clinical trial studies that support these three mechanisms for the neuroprotective action of FTY720 in ischemic stroke.

Vagotomy Improves Hypoxic Pulmonary Vasoconstriction in Rats Subjected to Brain Ischemia-Reperfusion Injury.

BACKGROUND: Pulmonary dysfunction is one of the critical complications of a stroke. However, it remains unclear whether the mechanism is caused by either neurogenic or inflammatory reactions. The present study aimed to determine the effect of cerebral ischemia-reperfusion injury and the role of the vagus nerve on hypoxic pulmonary vasoconstriction (HPV) in rats. METHODS: This study was performed at Shiraz University of Medical Sciences, Shiraz, Iran, 2018. Male Sprague Dawley rats (n=56) were divided into four groups, namely the sham, vagotomy (Vag), 1 hour of ischemia followed by 23 hours of reperfusion without vagotomy (I/R) and with vagotomy (I/R+Vag). Neurological deficit scores and total infarct volumes of brains were measured in the I/R and I/R+Vag groups. Pulmonary artery pressure and lung weight were continuously registered during ventilation with normoxic and hypoxic gases in the isolated lungs. The blood gas parameters and the lung malondialdehyde (MDA) level of each group were also evaluated. ANOVA, with Tukey's post hoc test and t test, was used to compare the variables in the experimental groups. RESULTS: The infarct volume of the brains in the I/R and I/R+Vag groups were similar. HPV in the I/R group was lower than those in the sham and Vag groups, while vagotomy reversed this response in the I/R+Vag group (P=0.004). In the I/R group, PO2 and pH were lower, and PCO2 was higher than those in the sham and Vag groups. The lung MDA level in the I/R group was higher than that in the Vag group (P=0.019). CONCLUSION: Brain ischemia-reperfusion injury decreased HPV independent of increased MDA in the lung, whereas vagotomy improved HPV by repairing the blood-gas barrier and oxygen sensing.

Lung injury in brain ischemia/reperfusion is exacerbated by mechanical ventilation with moderate tidal volume in rats.

Ischemic stroke is one of the most frequent causes of injury in the central nervous system which may lead to multiorgan dysfunction, including in the lung. The aim of this study was to investigate whether brain ischemia/reperfusion with or without mechanical ventilation leads to lung injury. Male Sprague-Dawley rats were assigned to four groups: Sham, 1-h brain ischemia (MCAO)/24-h reperfusion (I/R), mechanical ventilation with moderate tidal volume (MTV), and I/R+MTV. The pulmonary capillary permeability (Kfc) was measured in the isolated perfused lung. Mean arterial blood pressure (MAP), heart rate (HR), blood-gas variables, histopathological parameters, lung glutathione peroxidase, and TNF-α were measured. Kfc in the I/R, MTV, and I/R+MTV groups were higher than that in the Sham group. In the I/R, MTV, and I/R+MTV groups, arterial partial pressures of oxygen and the arterial partial pressure of oxygen/fraction of inspired oxygen ratios were lower, whereas arterial partial pressures of carbon dioxide were higher than those in the Sham group. The histopathological score in the I/R group was more than that in the Sham group, and in the MTV and I/R+MTV groups were higher than those in the Sham and I/R groups. Furthermore, there were stepwise rises in TNF-α in the I/R, MTV, and I/R+MTV groups, respectively. There was no significant difference in MAP between groups. However, HR in the MTV group was higher than that in the Sham group. Brain ischemia/reperfusion leads to pulmonary capillary endothelial damage and the impairment of gas exchange in the alveolar-capillary barrier, which is exacerbated by mechanical ventilation with moderate tidal volume partially linked to inflammatory reactions.

Right ventricular pressure elevated in one-kidney, one clip Goldblatt hypertensive rats.

Both renal and respiratory diseases are common with high mortality rate around the world. This study was the first to compare effects of two kidneys, one clip (2K1C) and one-kidney, one clip (1K1C) Goldblatt hypertension on right ventricular pressure during normal condition and mechanical ventilation with hypoxia gas. Male Sprague-Dawley rats were subjected to control, 2K1C, or 1K1C groups. Twenty-eight days after the first surgery, animals were anesthetized, and femoral artery and vein, and right ventricle cannulated. Systemic arterial pressure and right ventricular systolic pressures (RVSP) were recorded during ventilation the animals with normoxic or hypoxic gas. RVSP in the 1K1C group was significantly more than the control and 2K1C groups during baseline conditions and ventilation the animals with hypoxic gas. Administration of antioxidant Trolox increased RVSP in the 1K1C and control groups compared with their baselines. Furthermore, there was no alteration in RVSP during hypoxia in the presence of Trolox. This study indicated that RVSP only increased after 28 days induction of 1K1C but not 2K1C model. In addition, it seems that the response to hypoxic gas and antioxidants in 1K1C is more than 2K1C. These data also suggest that effects of 1K1C may partially be related to reactive oxygen species (ROS) pathways.

Dual effects of eugenol on the neuronal excitability: An in vitro study.

Besides its well-known actions on sensory afferents, eugenol also affects general excitability of the nervous system, but the mechanisms involved in the recent effect, especially through modulation of ion channels, have received much less attention. In this study, we studied the effects of eugenol on the excitability of central neurons of land snail Caucasotachea atrolabiata and tried to elucidate the underlying ionic mechanisms. The lower concentration of eugenol (0.5mM) reversibly reduced the frequency of spontaneous action potentials that was associated with elevation of threshold, reduction of maximum slope of rising phase and prolongation of actin potentials. These effects were mimicked by riluzole, suggesting that they might be mediated by inhibition of Na+ channels. Eugenol also prolonged the single-spike afterhyperpolarization and post stimulus inhibitory period, but these effects seemed to be consequent to action potential prolongation that indirectly augment Ca2+ inward currents and Ca2+-activated K+ currents. This concentration of eugenol was also able to prevent or abolish pentylenetetrazole-induced epileptiform activity. On the other hand, a higher concentration of eugenol (2mM) reversibly increased the frequency of action potentials and then induced epileptiform activity in majority of treated neurons. Several criteria suggest that the inhibition of K+ channels by higher concentration of eugenol and indirect augmentation of Ca2+ currents are central to the hyperexcitability and epileptiform activity induced by eugenol. Our findings indicate that while low concentration of eugenol could have antiepileptic properties, at higher concentration it induces epileptiform activity. It seems that does dependent inhibition of the ionic currents underlying rising and falling phases of action potential is relevant to the eugenol suppressant and excitatory actions, respectively.