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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)E 2 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 PGE 2 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Bipolar affective disorder is a chronic, severe, debilitating illness affecting 1-2% of the population. Valproate, along with lithium and carbamazepine, are the only drugs for which long-term efficacy has been established. However, these drugs are ineffective for, and not well tolerated by, a large number of patients and are also associated with teratogenicity and reproductive defects. Therefore, there is a substantial need to develop more effective anti-bipolar drugs. We have previously shown that valproate, like lithium, decreases intracellular inositol, which supports the inositol depletion hypothesis. We employed inositol depletion in yeast as a screening tool to identify potential new anti-bipolar medications. We show here that hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, ethylhexanoate, and methyloctanoate decrease intracellular inositol levels and increase the expression of INO1, the gene encoding myo-inositol-3-phosphate synthase (MIPS). Similar to valproate, these inositol-depleting carboxylic acids inhibited MIPS indirectly. A correlation was shown between cell growth inhibition and the increase in INO1 expression by the carboxylic acids, factors that were reversed in the presence of inositol. Inositol depletion in yeast may be exploited as an easy and inexpensive screening test for potential new inositol depleting anti-bipolar drugs.

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.

Background: Accumulating evidence suggests that nuclear factor (NF)-κB is involved in the pathophysiology of mood disorders. Objectives and Methods: We conducted two experimental protocols in rats to investigate the effects of a selective NF-κB inhibitor (JSH-23) on (i) lipopolysaccharide (LPS)-induced inflammation and (ii) on behavioral phenotypes in rat models of depression (sucrose consumption test and forced swim test) and mania (amphetamine-induced hyperactivity test). Additionally, we tested the effects of JSH-23 on levels of inflammatory components (interleukin-6, prostaglandin E2, nuclear phospho-p65, and tumor necrosis factor-α) in the brain. Results: Acute treatment with JSH-23 (10 mg/kg, intraperitoneally [ip]) led to potent anti-inflammatory effects in LPS-treated rats, including a diminished hypothermic response to LPS and a reduction in pro-inflammatory mediators' levels in the brain. Chronic treatment with JSH-23 (3 mg/kg, ip, once daily, for 14 days) resulted in robust antidepressant-like effects (increased sucrose consumption and decreased immobility time). The antidepressant-like effects of JSH-23 were mostly accompanied by a reduction in levels of pro-inflammatory mediators in the brain. On the other hand, JSH-23 did not reduce amphetamine-induced hyperactivity. Conclusions: Altogether, these data suggest that NF-κB may be a potential therapeutic target for pharmacological interventions for depression. [ABSTRACT FROM AUTHOR]

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.

Several studies support the notion that inflammation plays a role in the pathophysiology and treatment approaches of psychiatric illnesses, particularly mood disorders. Congruently, classic anti-inflammatory drugs were found efficacious in randomized clinical trials of patients with mood disorders. Moreover, accumulating data indicate that psychotropic drugs exhibit some anti-inflammatory effects. This study was undertaken to examine the efficacy of dexamethasone (a potent corticosteroid) and pentoxifylline (a methylxanthine drug with proven anti-tumor necrosis factor-α inhibitory activity) in behavioral models in rats, which were treated intraperitoneally with either dexamethasone or pentoxifylline for two weeks and then subjected to a battery of behavioral tests. Treatment with pentoxifylline, but not dexamethasone, was associated with antidepressant-like and anti-manic-like effects. The beneficial behavioral effects of pentoxifylline were accompanied by a prominent reduction in pro-inflammatory mediator levels in the brain. For the first time, the current work proves the efficacy of pentoxifylline against both mania-like and depressive-like behaviors. These results suggest that pentoxifylline may be a promising therapeutic intervention for patients with mood disorders. Taking into account the excellent tolerability profile of pentoxifylline in humans, it is warranted to conduct randomized clinical trials to investigate its therapeutic efficacy in patients with psychiatric disorders. [ABSTRACT FROM AUTHOR]

Mounting evidence suggests that immune-system dysfunction and inflammation play a role in the pathophysiology and treatment of mood-disorders in general and of bipolar disorder in particular. The current study examined the effects of chronic low-dose aspirin and low-dose lithium (Li) treatment on plasma and brain interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-treated rats. Rats were fed regular or Li-containing food (0.1%) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. On days 21 and 42 rats were injected with 1 mg/kg LPS or saline. Two h later body temperature was measured and rats were sacrificed. Blood samples, the frontal-cortex, hippocampus, and the hypothalamus were extracted. To assess the therapeutic potential of the combined treatment, rats were administered the same Li + aspirin protocol without LPS. We found that the chronic combined treatment attenuated LPS-induced hypothermia and significantly reduced plasma and brain cytokine level elevation, implicating the potential neuroinflammatory diminution purportedly present among the mentally ill. The combined treatment also significantly decreased immobility time and increased struggling time in the forced swim test, suggestive of an antidepressant-like effect. This preclinical evidence provides a potential approach for treating inflammation-related mental illness. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of a dry aqueous extract of Notobasis syriaca (N. syriaca) on lipopolysaccharide (LPS)-induced inflammation in rats. Methods: Rats were fed the dried extract [500 mg/(kg•d)] for three consecutive days and then were intraperitoneally injected with LPS (1 mg/kg). Two hours after LPS injection, rats were sacrificed and blood and brain regions were collected. Inflammatory mediators' levels in plasma and homogenates of brain regions were determined by ELISA. Results: Pretreatment with the N. syriaca extract resulted in significant anti-inflammatory effects (P<0.05), including: i) attenuated LPS-induced hypothermia; ii) decreased hypothalamus and hippocampus prostaglandin E2 levels in the LPStreated rats; and, iii) reduced hypothalamus and hippocampus interleukin-6 and tumor necrosis factor-αlevels in the LPS-treated rats. Conclusions: These results suggest that N. syriaca possesses anti-inflammatory properties. Thus, it is possible that long-term consumption of this plant may result in beneficial pharmacological effects. [ABSTRACT FROM AUTHOR]