Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis

It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor α (PPARα), here, we established that oral administration of gemfibrozil preserved the integrity of blood–brain barrier (BBB) and blood–spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα–/– mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARβ (formerly PPARδ), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα–/– EAE mice, but not PPARβ–/– EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα

Selective Disruption Of Tlr2-Myd88 Interaction Inhibits Inflammation And Attenuates Alzheimer\u27S Pathology

Induction of TLR2 activation depends on its association with the adapter protein MyD88. We have found that TLR2 and MyD88 levels are elevated in the hippocampus and cortex of patients with Alzheimer\u27s disease (AD) and in a 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from a therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. Interestingly, WT TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, dsRNA, bacterial lipopolysaccharide, flagellin, or CpG DNA. After intranasal administration, WT TIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, WT TIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to its effects in 5XFAD mice, WT TIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of the activated status of 1 component of the innate immune system by WT TIDM peptide may be beneficial in AD as well as other disorders in which TLR2/MyD88 signaling plays a role in disease pathogenesis

Protection of Mice from Controlled Cortical Impact Injury by Food Additive Glyceryl Tribenzoate

Despite intense investigations, no effective therapy is available to halt the pathogenesis of traumatic brain injury (TBI), a major health concern, which sometimes leads to long-term neurological disability, especially in war veterans and young adults. This study highlights the use of glyceryl tribenzoate (GTB), a flavoring ingredient, in ameliorating the disease process of controlled cortical impact (CCI)-induced TBI in mice. Oral administration of GTB decreased the activation of microglia and astrocytes to inhibit the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of TBI mice. Accordingly, GTB treatment protected and/or restored synaptic maturation in the hippocampus of TBI mice as revealed by the status of PSD-95, NR-2A and GluR1. Furthermore, oral GTB also reduced the size of lesion cavity in the brain of TBI mice. Finally, GTB treatment improved locomotor functions and protected spatial learning and memory in TBI mice. These results outline a novel neuroprotective property of GTB which may be beneficial in treatment of TBI

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Improves Cognitive Functions in Mice after Controlled Cortical Impact Injury

Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults and war veterans. Although research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of an effective therapy to halt the pathogenesis of brain injury. Earlier, we reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson’s disease and Alzheimer’s disease. This study was undertaken to examine the therapeutic efficacy of NaB in a controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and to inhibit the expression of inducible nitric oxide synthase (iNOS) in the hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of the lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displaying a substantial reduction in depression-like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI

Cinnamon and Its Metabolite Sodium Benzoate Attenuate the Activation of p21rac and Protect Memory and Learning in an Animal Model of Alzheimer's Disease.

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in attenuating oxidative stress and protecting memory and learning in an animal model of Alzheimer's disease (AD). NaB, but not sodium formate, was found to inhibit LPS-induced production of reactive oxygen species (ROS) in mouse microglial cells. Similarly, NaB also inhibited fibrillar amyloid beta (Aβ)- and 1-methyl-4-phenylpyridinium(+)-induced microglial production of ROS. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on ROS production by mevalonate, and geranylgeranyl pyrophosphate, but not cholesterol, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the antioxidant effect of NaB. Furthermore, we demonstrate that an inhibitor of p21rac geranylgeranyl protein transferase suppressed the production of ROS and that NaB suppressed the activation of p21rac in microglia. As expected, marked activation of p21rac was observed in the hippocampus of subjects with AD and 5XFAD transgenic (Tg) mouse model of AD. However, oral feeding of cinnamon (Cinnamonum verum) powder and NaB suppressed the activation of p21rac and attenuated oxidative stress in the hippocampus of Tg mice as evident by decreased dihydroethidium (DHE) and nitrotyrosine staining, reduced homocysteine level and increased level of reduced glutathione. This was accompanied by suppression of neuronal apoptosis, inhibition of glial activation, and reduction of Aβ burden in the hippocampus and protection of memory and learning in transgenic mice. Therefore, cinnamon powder may be a promising natural supplement in halting or delaying the progression of AD

Some Results of Ozone Measurements Taken during the Indo-USSR Ozone Intercomparison during 1983

147-158An Indo-Soviet collaborative ozone intercomparison experiment was conducted at the Thumba Equatorial Rocket Launching Station (TERLS) during Mar 1983. The India Meteorological Department (lMD) actively participated in the experiment and especially established total ozone, Umkehr, surface ozone and balloon ozonesonde stations at TERLS for this experiment. Earlier total ozone observations by Dobson instrument were taken at TERLS for a short spell during 1-16 Dec 1982. In addition, IMD ozone network made a special effort to make uninterrupted observations during 23 Feb-5 Apr. 1983. During the period, a total of 11 stratospheric balloon soundings were made by IMD from TERLS and radiosonde station (Trivandrum) for the measurement of vertical profiles of ozone temperature, humidity and winds. These data have been utilized to study various interesting features of ozone variations over India, with particular reference to the effect of the Western Disturbance on the total ozone over India. Vertical ozone profile data obtained from Umkehr observations and balloon ozonesondes have been utilized to establish a mean ozone profile over TERLS for the first time. The experiment has provided a unique data base to analyse ozone anomaly over Kodaikanal and to put forward a scientific explanation for it. The vertical ozone data up to tropopause and the surface ozone data have also been utilized to study tropospheric ozone over India

Oral administration of cinnamon powder and NaB inhibits neuronal apoptosis <i>in vivo</i> in the hippocampus of Tg5XFAD mice.

<p>Tg mice (6 months old) were treated with cinnamon (100 mg/kg body wt/d) and NaB (50 mg/kg body wt/d) orally. After 2 months of treatment, hippocampal sections were double-labeled for TUNEL and NeuN. Results represent analysis of two hippocampal sections of each of six mice per group. Tissue lysates were analyzed for cleaved caspase 3 by Western blot (B & C, cinnamon; D & E, NaB). Bands were scanned and results presented as relative to non-Tg (C, cinnamon; E, NaB). Results represent mean ± SEM of four mice per group. ^<i>a</i><i>p < 0</i>.<i>001 vs non-Tg;</i>^<i>b</i><i>p < 0</i>.<i>001 vs Tg</i>. F) Hippocampal sections were double-labeled for phospho-Tau and NeuN. Results represent analysis of two hippocampal sections of each of six mice per group. G) Tissue lysates were analyzed for phospho-Tau and total Tau by Western blot. H) Bands were scanned and results presented as relative to non-Tg. Results represent mean ± SEM of four mice per group. ^<i>a</i><i>p < 0</i>.<i>001 vs non-Tg;</i>^<i>b</i><i>p < 0</i>.<i>05 vs Tg</i>.</p