Chronic Treatment with Nigella sativa Oil Exerts Antimanic Properties and Reduces Brain Inflammation in Rats.

Nigella sativa (NS) is a native herb consumed habitually in several countries worldwide, possessing manifold therapeutic properties. Among them, anti-inflammatory features have been reported, presumably relating to mechanisms involved in the nuclear factor kappa-B pathway, among others. Given the observed association between neuroimmune factors and mental illness, the primary aim of the present study was to examine the effects of chronic NS use on manic-like behavior in rats, as well as analyze levels of brain inflammatory mediators following NS intake. Using male and female rats, baseline tests were performed; thereafter, rats were fed either regular food (control) or NS-containing food (treatment) for four weeks. Following intervention, behavioral tests were induced (an open field test, sucrose consumption test, three-chamber sociality test, and amphetamine-induced hyperactivity test). Subsequently, brain samples were extracted, and inflammatory mediators were evaluated, including interleukin-6, leukotriene B4, prostaglandin E2, tumor necrosis factor-α, and nuclear phosphorylated-p65. Our findings show NS to result in a marked antimanic-like effect, in tandem with a positive modulation of select inflammatory mediators among male and female rats. The findings reinforce the proposed therapeutic advantages relating to NS ingestion.

Montelukast induces beneficial behavioral outcomes and reduces inflammation in male and female rats.

Background: Accumulative data links inflammation and immune dysregulation to the pathophysiology of mental disorders; little is known regarding leukotrienes' (LTs) involvement in this process. Circumstantial evidence suggests that treatment with leukotriene modifying agents (LTMAs) such as montelukast (MTK) may induce adverse neuropsychiatric events. Further methodic evaluation is warranted. Objective: This study aims to examine behavioral effects, as well as inflammatory mediator levels of chronic MTK treatment in male and female rats. Methods: Depression-like phenotypes were induced by exposing male and female rats to a chronic unpredictable mild stress (CUMS) protocol for four weeks. Thereafter, rats were treated (intraperitoneally) once daily, for two weeks, with either vehicle (dimethyl sulfoxide 0.2 ml/rat) or 20 mg/kg MTK. Following treatment protocols, behavioral tests were conducted and brain regions were evaluated for inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and prostaglandin (PG) E2. Results: Overall, MTK did not invoke negative behavioral phenotypes (except for an aggression-inducing effect in males). Numerous positive behavioral outcomes were observed, including reduction in aggressive behavior in females and reduced manic/hyperactive-like behavior and increased sucrose consumption (suggestive of antidepressant-like effect) in males. Furthermore, in control males, MTK increased IL-6 levels in the hypothalamus and TNF-α in the frontal cortex, while in control females it generated a robust anti-inflammatory effect. In females that were subjected to CUMS, MTK caused a prominent reduction in TNF-α and IL-6 in brain regions, whereas in CUMS-subjected males its effects were inconsistent. Conclusion: Contrary to prior postulations, MTK may be associated with select beneficial behavioral outcomes. Additionally, MTK differentially affects male vs. female rats in respect to brain inflammatory mediators, plausibly explaining the dissimilar behavioral phenotypes of sexes under MTK treatment.

A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats.

AIM: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. MAIN METHODS: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. KEY FINDINGS: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. SIGNIFICANCE: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

Inhibition of cyclooxygenase-1 does not reduce mortality in post-ischemic stroke rats.

BACKGROUND: Ischemic stroke is one of the leading causes of mortality and morbidity. The currently available non-invasive therapeutic options are not sufficiently efficacious. Post-ischemic brain is characterized by a prominent inflammatory response. Little is known about the involvement of cyclooxygenase (COX)-1 in the pathophysiology of ischemic stroke. OBJECTIVE: This study was undertaken to examine the effects of a highly selective COX-1 inhibitor - mofezolac - on clinical outcomes and brain inflammatory markers in post-stroke rats. METHODS: Stroke was induced by subjecting rats to permanent middle cerebral artery occlusion (MCAO). Control rats underwent a sham surgery. Rats were treated with mofezolac (50 mg/kg, intraperitoneally [ip]) once daily for 14 days. Control animals were treated with vehicle. Body temperature (BT), neurological score (NS) and cumulative mortality were monitored at different time points. At the end of the experiment, rats were euthanized and three brain regions (hypothalamus, hippocampus and frontal cortex) were extracted. Levels of interleukin (IL)-6, prostaglandin (PG)E2 and tumor necrosis factor (TNF)-α in these brain regions were determined by ELISA kits. RESULTS: BT, NS and cumulative mortality were all significantly higher in post-MCAO rats than in sham-operated rats, irrespective of the treatment given. BT, NS and mortality rate did not differ significantly between mofezolac-treated and vehicle-treated sham-operated animals. BT was significantly lower in mofezolac-treated as compared to vehicle-treated post-MCAO rats. Mofezolac did not significantly alter NS in post-MCAO rats at any time-point. Cumulative 14-day mortality was non-significantly higher in mofezolac-treated as compared to vehicle-treated post-MCAO rats (48 % vs. 21 %, respectively; P = 0.184). Mostly, IL-6 and TNF-α levels did not differ between post-MCAO and sham-operated rats and were not affected by mofezolac treatment. In contrast, mofezolac significantly decreased PGE2 levels in post-MCAO rats' brains. CONCLUSION: Overall, these results suggest that chronic treatment with the selective COX-1 inhibitor mofezolac did not reduce morbidity or mortality in post-stroke rats.

Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats.

Stroke is a leading cause of mortality and morbidity worldwide. Few therapeutic options with proven efficacy are available for the treatment of this disabling disease. Lithium is the gold standard treatment for bipolar disorder. Moreover, lithium has been shown to exhibit neuroprotective effects and therapeutic efficacy as a treatment of other neurological disorders. This study was undertaken to examine the effects of lithium on brain inflammatory mediators levels, fever, and mortality in postischemic stroke rats. Ischemic stroke was induced by occlusion of the mid cerebral artery (MCAO). Pretreatment with a single dose of lithium at 2 hours before MCAO induction significantly reduced the elevation in interleukin- (IL-) 6 and prostaglandin E2 levels in brain of post-MCAO rats, as compared to vehicle-treated animals. On the other hand, lithium did not affect the elevation in IL-1α, IL-10, IL-12, and tumor necrosis factor-α levels in brain of post-MCAO rats. Moreover, pretreatment with lithium did not alter post-MCAO fever and mortality. These results suggest that acute pretreatment with a single dose of lithium did not markedly affect post-MCAO morbidity and mortality in rats.

Effectiveness of motor learning coaching in children with cerebral palsy: a randomized controlled trial.

OBJECTIVE: To evaluate effectiveness of motor learning coaching on retention and transfer of gross motor function in children with cerebral palsy. DESIGN: Block randomized trial, matched for age and gross motor function. SETTING: Coordinated, multinational study (Israel, Jordan and Palestinian Authority) in schools and rehabilitation centers. SUBJECTS: 78 children with spastic cerebral palsy, gross motor functional levels II and III, aged 66 to 146 months. INTERVENTIONS: 1 hr/day, 3 days/week for 3 months treatment with motor learning coaching or neurodevelopmental treatment: two groups. MAIN MEASURES: Gross motor function Measure (GMFM-66), stair-climbing mechanical efficiency (ME) and parent questionnaire rating their child's mobility. Immediate treatment effects were assessed after 3 months and retention determined from follow-up measurements 6 months after treatment. RESULTS: GMFM-66, ME and parent questionnaires were obtained from 65, 31 and 64 subjects, respectively. Although both groups increased GMFM-66 score over 3 months, measurements 6 months later indicated retention was significantly superior by 2.7 in the motor learning coaching children of level-II. Similar retention trend was evident for ME, increasing 6 months after motor learning coaching by 1.1% and declining 0.3% after neurodevelopmental treatment. Mobility performance in the outdoors and community environment increased 13% from 3 to 9 months after motor learning coaching and decreased 12% after neurodevelopmental treatment. Minor group differences occurred in children of level-III. CONCLUSIONS: In higher functioning children with cerebral palsy, the motor learning coaching treatment resulted in significantly greater retention of gross motor function and transfer of mobility performance to unstructured environments than neurodevelopmental treatment.

Prediction of mechanical efficiency from heart rate during stair-climbing in children with cerebral palsy.

Measuring mechanical efficiency (ME) is potentially useful to assess motor performance in individuals with physical disabilities. The purpose of this study was to determine the accuracy of predicting ME from heart rate (HR) during a self-paced stair-climbing test in children with a range of motor abilities. The participants were 12 normally developed children (ND) and 24 with cerebral palsy (CP), ranging in age from 5 to 15 years (mean: 8 years). Five were at level II, 11 at level III and 8 at level IV according to the gross motor function classification system. ME was calculated as the ratio of external work to O(2) uptake (VO(2) ml/min) measured or predicted from HR. The absolute values of VO(2) and HR during stair-climbing were not significantly correlated. However, the correlation between values above resting (dVO(2) and dHR) was significant (r=0.61). Furthermore, when including body weight as a second variable the prediction of dVO(2) was significantly improved (r=0.85). This resulted in a high correlation (r=0.96) between measured and predicted net ME (ME(net)). Predicted ME(net) for 25 stair-climbing tests repeated after an average of 6 months resulted in an r-value of 0.92 with predicted ME(net) of the first test. This study demonstrates that ME(net) during stair-climbing can be predicted in children with a broad range of motor abilities from dHR and may be a simple tool to help define developmental stages or evaluating intervention efficacy.

Effects of estrogen against LPS-induced inflammation and toxicity in primary rat glial and neuronal cultures.

Several lines of evidence link inflammation with neurodegenerative diseases, which are aggravated by the age-related decline in estrogen levels in postmenopausal women. Lipopolysaccharide (LPS) is used widely to stimulate glial cells to produce pro-inflammatory mediators such as NO, PGE(2), and TNF-alpha, and was found to be toxic in high doses. We examined the effects of a physiological dose of 17beta-estradiol (E2) against LPS-induced inflammation and toxicity (cell death) in rat primary glial and neuronal cultures. Cultures were treated with 0.1 nM E2 for 24 h and then exposed to LPS 0.5-200 microg/ml for another 24 h. Levels of NO, PGE(2), and TNF-alpha in the culture medium were determined by the Griess reaction assay, radio-immunoassay, and enzyme-linked immunoassay, respectively. Cell death was quantified by measuring the leakage of lactate dehydrogenase (LDH) into the medium from dead or dying cells using the non-radioactive cytotoxicity assay. E2 significantly reduced the LPS-induced increase in NO and TNF-alpha (but not PGE(2)) production in glial cells. PGE(2) and TNF-alpha were undetectable in neuronal cultures, while only basal levels of NO were detected, even after stimulation with LPS. Moreover, pretreatment with E2 significantly reduced LPS-induced cell death, as measured by the release of LDH, in both glial and neuronal cultures. These results suggest that the neuroprotective effects attributed to E2 are derived, at least in part, from its anti-inflammatory and cytoprotective effects in both glial and neuronal cells.

Comparison of efficacy of Adeli suit and neurodevelopmental treatments in children with cerebral palsy.

This study compared the efficacy of Adeli suit treatment (AST) with neurodevelopmental treatment (NDT) in children with cerebral palsy (CP). Twenty-four children with CP, Levels II to IV according to the Gross Motor Function Classification System (GMFCS), were matched by age and functional status and randomly assigned to the AST or NDT treatment groups. In the AST group (n=12; eight males, four females; mean age 8.3 y [SD 2.0]), six children had spastic/ataxic diplegia, one triplegia and five spastic/mixed quadriplegia. In the NDT group (n=12; nine males, three females; mean age 8.1 y [SD 2.2]), five children had spastic diplegia and seven had spastic/mixed quadriplegia. Both groups were treated for 4 weeks (2 hours daily, 5 days per week, 20 sessions). To compare treatments, the Gross Motor Function Measure (GMFM-66) and the mechanical efficiency index (EIHB) during stair-climbing were measured at baseline, immediately after 1 month of treatment, and 10 months after baseline. The small but significant time effects for GMFM-66 and EIHB that were noted after 1 month of both intensive physiotherapy courses were greater than expected from natural maturation of children with CP at this age. Improvements in motor skills and their retention 9 months after treatment were not significantly different between the two treatment modes. Post hoc analysis indicated a greater increase in EIHB after 1 month (p=0.16) and 10 months (p=0.004) in AST than that in NDT, predominantly in the children with higher motor function (GMFCS Levels II and III). The results suggest that AST might improve mechanical efficiency without a corresponding gain in gross motor skills, especially in children with higher levels of motor function.

Inhibition of prostaglandins does not reduce the cardiovascular changes during endotoxemia in rats.

Vasodilatory prostanoids, such as prostacyclin and PGE2, and pro-inflammatory cytokines are known to play a central role in the pathogenesis of endotoxemia. This study was undertaken to elucidate whether indomethacin (INDO), a non-selective COX inhibitor, has protective effects against the cardiovascular alterations that occur during endotoxemia. Sprague-Dawley rats were injected intraperitoneally with 15 mg/kg lipopolysaccharide (LPS). LPS injection led to a prominent decrease in cardiac left ventricular end diastolic area (LVEDA) and increased LV fractional shortening (FS), as measured by echocardigraphy. LPS also led to a significant increase in plasma and myocardial TNF-alpha and IL-1beta levels, and elevated plasma and hypothalamic levels of PGE2. Neither the decrease in LVEDA and the increase in FS, nor the elevation in plasma and myocardial cytokine levels were altered by INDO (10 mg/kg). On the other hand, pretreatment with INDO significantly reduced the elevation in PGE2 and the hypothermia induced by LPS. Taken together, this study demonstrates that solely inhibiting the production of PGE2 is not sufficient to reduce the cardiovascular alteration seen in endotoxemia.

[Effect of physical training on postural control of elderly].

BACKGROUND: Preservation of balance in the elderly is fundamental to maintaining functional independence. Balance impairments have a tremendous impact on health care costs and quality of life. Fall prevention programs are an important health strategy, consequently there is a general need to develop effective and practical exercise programs that improve balance in the elderly. OBJECTIVE: To explore whether stability can be improved through exercise in inactive old subjects and to determine whether specific balance training proves to be more beneficial to retaining balance than strength training. METHODS: A randomized controlled study was conducted with 42 healthy elderly individuals. They were randomly allocated to three groups: Balance training (BT), Isometric training (IT) and Control (CG) received no intervention; each group consisted of 14 members. "Static" and "dynamic" postural stability were evaluated for seven postural conditions in upright standing before and immediately after 3 months of intervention using a force platform, and an isokinetic dynamometer used to determine whether the training improved muscle strength. RESULTS: The BT group significantly improved their forward-backward stability limits (maximal body lean) post intervention compared with other groups. Plantar and dorsiflexion isometric strength remained the same in all groups. No significant improvement was found in COP based measures in upright standing in all study groups, apart from the BT group that significantly improved parameters in performance with eyes open and during standing on a foam. BT subjects improved their self-confidence post intervention in 64.2%, while IT subjects improved in only 35.7%. CONCLUSIONS: Balance exercises appear to improve balance in the elderly, especially extending the boundaries of their stability a more dynamic component of balance. However it remains to be determined whether the lack of difference between groups in COP measures in upright standing ("static balance") was due to the short period of intervention, small sample size, unchallenged exercise regime or due to the inability of elderly individuals to improve their sway in upright standing.

Effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on cardiovascular alterations in endotoxemia.

Prostanoids and cytokines are known to play a pivotal role in the mechanisms leading to endotoxin-induced cardiovascular failure. We investigated the effect of nimesulide (NIM), a selective cyclooxygenase-2 (COX-2) inhibitor, on the cardiovascular alterations occurring during endotoxemia, and on prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in endotoxemic rats. NIM significantly reduced endotoxin-induced elevation of plasma and myocardial levels of TNF-alpha, but not those of IL-1beta. Searching for the mechanism underlying the anti-TNF-alpha effect of NIM, it was found that the drug reduced nuclear factor kappa B activation through diminished nuclear levels of p-65 accompanied by a protective effect against the cardiovascular alterations and mortality seen during endotoxemia. In addition, the inhibitory effect of NIM on endotoxin-induced elevation in plasma and hypothalamic levels of PGE2 was noteworthy, and this may suggest that the large amounts of PGE2 observed during endotoxemia are mainly produced via COX-2.

Aging-induced shifts from a reliance on sensory input to muscle cocontraction during balanced standing.

BACKGROUND: Peripheral sensation is the most important sensory system in the maintenance of upright posture in all age groups. With aging, visual and somatosensory processing change their prospective contribution to the maintenance of quiet standing, at debated percentages. Aging is associated with a decrease in balance abilities that, in turn, increases the risk of falling. We used force plate data to show that, with aging, while vision plays a significant role in regulating postural stability (PS), the individual's perception of his/her stability becomes more significant than vision. Moreover, under experimental conditions, electromyography (EMG) of the ankle musculature of elderly people reveals the adoption of a different strategy, a cocontraction strategy, with or without visual input. The aim of this study was to look at two distinct age groups to determine whether or not a shift takes place in the sensory modality typically relied on while maintaining PS during a static, postural-related task. METHOD: The participants comprised two groups: a "young" (Y) group of 20 people aged 20-35, and an "old" (O) group of 32 people aged 65-84. The role of vision was tested with regard to two differently sized bases of support. They were tested during quiet upright standing on a single force plate in wide base and then in narrow base conditions. Surface EMG was recorded from the tibialis anterior, soleus, rectus femoris, and semitendinous muscles. RESULTS: The older group differed from the younger group when performing the task under the narrow base condition. When participants stood naturally, our EMG data indicated that, unlike the Y group, the O group used cocontraction around the ankle in order to deal with changing conditions and sensory inputs. Significant increases were found in the area, length, and mean velocity of body sway in the older group as compared with the younger group. DISCUSSION: The visual contribution to postural stabilization is significantly greater in the younger population than in the elderly population. Across the older group, lack of vision seemed to interfere less with PS; however, the EMG data indicated that, unlike the Y group, the O participants used cocontraction around the ankle in order to deal with changing conditions and sensory inputs. CONCLUSION: To cope with the deterioration in their sensory input and processing ability, elderly individuals seemed to have developed a strategy of stiffening and freezing their lower legs during upright standing.

Involvement of eicosanoids in the hypothermic response to lipopolysaccharide during endotoxemia in rats.

Hypothermia is one of the prominent features of the acute phase response to endotoxin (LPS). This study was undertaken to elucidate the effects of the COX-inhibitor Indomethacin (INDO) and the selective FLAP inhibitor MK-886 on LPS-induced hypothermia, mortality and increase in production of hypothalamic prostaglandin E(2) (PGE(2)) and leukotriene during endotoxemia. It has been demonstrated that INDO and MK-886 significantly attenuate the hypothermia induced by LPS, but MK-886 has a lesser (protective) effect than INDO. Only INDO was found to attenuate significantly the hyperthermic response to LPS. Furthermore, INDO significantly reduced the elevation in hypothalamic PGE(2) levels. MK-886 significantly reduced the elevation in hypothalamic leukotriene production only when LPS was given in a dose of 1mg/kg. Both drugs failed to reduce the elevation in plasma TNF-alpha and mortality induced by LPS. We conclude that in rats, febrile response to endotoxin involves many inflammatory mediators. However, it seems that PGE(2) and leukotrienes do not have a pivotal role in the mechanism of LPS-induced mortality.

The effect of high and low ambient temperatures on PGE2 and TNF-alpha production by rat glial brain cultures.

This study was undertaken to investigate the effect of changes in incubation temperature on PGE(2) and TNF-alpha production by rat glial brain cultures after LPS stimulation. One-hour incubation at temperatures of 4 degrees C, 37 degrees C, 39 degrees C and 42 degrees C were used. Treatment of cultures with 10 microg/ml LPS from Escherichia coli caused a significant elevation of PGE(2) production 24 h after incubation at control temperatures of 37 degrees C and the experimental temperatures of 4 degrees C, 39 degrees C and 42 degrees C. While high ambient temperatures of 39 degrees C and 42 degrees C reduced LPS-stimulated production, compared to exposure to 37 degrees C, exposure to 4 degrees C did not do so. On the other hand, exposure of the cultures to a temperature of 39 degrees C and 42 degrees C for 1 h did not alter LPS-stimulated TNF-alpha production, while exposure to a temperature of 4 degrees C significantly reduced this elevation.

LF 16-0687 Ms, a new bradykinin B2 receptor antagonist, improves neurologic outcome but not brain tissue prostaglandin E2 release in a rat model of closed head trauma combined with ethanol intoxication.

BACKGROUND: LF 16-0687 Ms previously was reported to improve Neurological Severity Score (NSS) and decrease cerebral edema and prostaglandin E(2) (PGE(2)) release after closed head trauma (CHT) in rats. Here, we examined whether these beneficial effects of LF 16-0687 Ms are altered when CHT is accompanied by acute ethanol administration. METHODS: Six groups of rats (n = 8 per group) were examined during combination of the following experimental conditions: CHT versus sham operation, LF 16-0687 Ms 3 mg/kg subcutaneously versus saline, and ethanol 2 g/kg versus saline. RESULTS: After CHT, brain water content decreased and NSS improved with ethanol + LF 16-0687 Ms as compared with values after saline or ethanol. PGE(2) release decreased with ethanol (147 +/- 59 pg/mg tissue) but not with ethanol + LF 16-0687 Ms (286 +/- 194 pg/mg tissue). CONCLUSION: Ethanol does not affect the improvement of NSS and the decrease of cerebral edema seen with LF 16-0687 Ms after CHT, but does reverse the ability of LF 16-0687 Ms to minimize the increase of PGE(2) release. In intoxicated patients, bradykinin antagonist therapy may improve post-CHT outcome without altering PGE(2) release.