Neuroprotective Effect of Clobenpropit against Lipopolysaccharide-Induced Cognitive Deficits via Attenuating Neuroinflammation and Enhancing Mitochondrial Functions in Mice

Clobenpropit (CLO), an antagonist on histamine H3 receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. CLO (1 and 3 mg/kg, p.o.) was treated continually for 30 days, and neurotoxicity was induced by four doses of LPS (250 µg/kg, i.p.). The radial arm maze (RAM) was used to access memory behaviors. After the REM test, brain tissue was collected from each mouse to estimate pro-inflammatory cytokines (TNFα and IL6), anti-inflammatory cytokines (TGF-β1 and IL-10), cyclooxygenase-2 (COX 2), and mitochondrial respiratory chain complex (MRCC- I, II and IV) enzymes. CLO treatment reversed the LPS-induced behavioral deficits by a significant reduction in time taken to consume all five bites (TTB), working memory error (WME), and reference memory error (REM) in the REM test. Regarding neuroinflammation, it attenuated the release of COX, TNF-α, and IL-6, and augmented TGF-β1 and IL-10 levels in the brain. Reversal of LPS-induced brain MRCC (I, II, and IV) levels also resulted with CLO treatment. From these findings, CLO promises neuroprotection against LPS-induced cognitive deficits by ameliorating neuroinflammation and restoring the MRCC enzymes in mice.

The Effects of Glucagon and Insulin Combination toward on Neurodegeneration Following Traumatic Brain Injury in Rat Model

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability in the productive age. Glutamate excitotoxicity and hyperglycemia those occur following TBI are among the factors those influence secondary brain injury. AIM: This study aimed to determine the effect of glucagon and insulin combination on neuronal necrosis following TBI. METHODS: A total of 28 male wistar rats were randomized into four experimental groups: placebo, insulin, glucagon, and combination of glucagon and insulin. Each animal underwent controlled cortical impact model of TBI. The blood glucose and glutamate levels were measured before and 4 h following TBI. The brain tissues were collected to evaluate neuronal necrosis. RESULTS: Glucagon or glucagon and insulin combination were able to prevent the increased of blood glutamate levels following TBI (p < 0.05). Glucagon administration was associated high blood glucose level (198.10 ± 32.58 mg/dL); a combination with insulin was able to minimize the increased of blood glucose level (166.53 ± 18.48 mg/dL). Combination of glucagon and insulin had a lower number of neuronal necrosis compare to the other groups (p < 0.005). CONCLUSION: The combination of glucagon and insulin potentially exhibit neuroprotection effect on rats following TBI as being demonstrated by lower number of neuronal necrosis. This finding further indicates the role of glucose homeostasis in neuroprotection.

Experimental porcine astrovirus type 3-associated polioencephalomyelitis in swine

Porcine astrovirus type 3 (PoAstV3) is an emerging virus in the family Astroviridae that has been recently associated with polioencephalomyelitis/encephalitis. Herein, we describe the experimental oral and intravenous inoculation of an infectious central nervous system (CNS) tissue homogenate containing PoAstV3 to cesarean-derived, colostrum-deprived pigs, and the subsequent development of clinical signs, histologic lesions, specific humoral immune response, and detection of viral particles by electron microscopy (EM) and viral RNA by RT-qPCR (reverse transcriptase quantitative polymerase chain reaction) and in situ hybridization (ISH). IgG against a portion of the PoAstV3 ORF2 capsid was first detected at 7 days post-inoculation (DPI) in 2 of 4 inoculated animals and in all inoculated animals by 14 DPI. At 21 and 28 DPI, 2 of 4 inoculated animals developed ataxia, tetraparesis, and/or lateral recumbency. All inoculated animals had histologic lesions in the CNS including perivascular lymphoplasmacytic cuffs, multifocal areas of gliosis with neuronal necrosis, satellitosis, and radiculoneuritis, and PoAstV3 RNA as detected by RT-qPCR within multiple anatomic regions of the CNS. Consistent viral structures were within the soma of a spinal cord neuron in the single pig examined by EM. Of note, PoAstV3 was not only detected by ISH in neurons of the cerebrum and spinal cord but also neurons of the dorsal root ganglion and nerve roots consistent with viral dissemination via axonal transport. This is the first study reproducing CNS disease with a porcine astrovirus strain consistent with natural infection, suggesting that pigs may serve as an animal model to study the pathogenesis of neurotropic astroviruses.

Herbal Plethora For Management Of Neurodegenerative Disorders: An Invigorating Outlook

Objective: Oxidative stress, proteasomal impairment, mitochondrial dysfunction, and accumulation of abnormal protein aggregates have shovelled a major section of senior population towards neurodegenerative disorders. Although age, genetic and environmental factors are thought to play a significant role, drug abuse is considered to be a potent trigger in Parkinsonism among the young generation. The present study is a critical examination on herbal resources for attenuation of neurodegeneration. Materials and Methods: The following electronic databases have been used to search for literature: MEDLINE, Scopus, PubMed and EMBASE Results : Paying heed to the prevalence in neurodegenerative disorders-Alzheimer’s & Parkinson’s; the current review encompasses the pathogenesis of neurodegeneration at cellular level and possible prospects to overcome the challenge sailing through the ocean of herbal boon. The United States-Alzheimer’s Association states, deaths attributable to heart disease in the country fell by 11% between 2000 and 2015, while deaths from neurodegenerative diseases increased by a staggering 123% making it, the world’s sixth leading cause of death. The irreversible pathological damage amounts to cognitive loss, dementia, Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) Alzheimer’s disease (AD). Various herbal drugs like Brahmi, Shankhpushpi and Amla are reported to be rich in phytoconstituents like, flavonoids, glycosides, alkaloids, fatty acids, sterols, tannins, saponins, and terpenes that have remarkable antioxidant potential and could be explored for the same to prevent neuronal necrosis. Conclusion: It is also believed that herbal medicines are more effective and less toxic than synthetic drugs.

Increased expression of fragmented tRNA promoted neuronal necrosis

Neuronal necrosis induced by excessive glutamate release is well known to contribute morbidity and mortality in ischemic stroke. Over the past decades, strategies on targeting glutamate receptor did not achieve desirable clinical outcomes. Finding the downstream mechanism of the glutamate receptor activation may provide new targets to suppress the cell death. Previously, our study demonstrated that the increase of H3K4 trimethylation (H3K4me3) played a key detrimental role on neuronal necrosis; however, the mechanism of this histone modification is unclear. Through a genome-wide small RNA sequencing, we identified several tRNA-derived fragments (tRFs) and piwi-interacting RNA (piRNAs) species were enriched in glutamate-induced neuronal necrosis in rat primary neuron cultures, and this enrichment was dependent on the H3K4me3 increase. Strikingly, when we transfected several synthesized tRFs and piRNA species into neurons, the tRFs but not the piRNAs induced neuron swelling and death. The cell death morphology recapitulated neuronal necrosis induced by glutamate. For the cytotoxic effect of tRFs, our data suggested that protein synthesis was inhibited likely through induction of ribosomal stalling. By proteomic analysis of tRFs effect, the most affected pathway was enriched in the mitochondrial metabolism. Consistently, mitochondrial fragmentation was increased in neuronal necrosis, and suppression of mitochondrial fission by genetic manipulation or drug rescued neuronal necrosis. Using our previously established Drosophila model of neuronal necrosis, we found that inhibition of small RNA transcription, blocking RNA transport from nucleus to cytosol, or knocking down Ago1/2 to suppress the RNA interference effect, all rescued the fly death, suggesting transcription and processing of small RNAs contribute to neuronal necrosis. Together, these results indicate that the abnormal transcription of tRFs may play a key role downstream of the H3K4me3 increase. This provides a potential new strategy to suppress neuronal necrosis.

Encephalopathy caused by Talisia esculenta intoxication in pregnant ewes and their newborn lambs

An outbreak of acute encephalopathy occurred in pregnant ewes and their newborn lambs associated with consumption of Talisia esculenta fruits and bark. Clinical signs in 5 adult pregnant ewes included drooling, bloat, tachypnea, depression, ataxia, body shaking, difficulty in rising, and recumbency. Three neonatal lambs born to some of those ewes had similar clinical signs. No significant gross abnormalities were observed on autopsy. Histologically, neuronal necrosis, axonal and dendritic swelling, and loss of Purkinje neurons were observed in the cerebellum. The observation of similar neurologic clinical signs and lesions in pregnant ewes and their neonatal lambs suggests that the toxic principle of T. esculenta crosses the placenta and reaches the fetus.

Verminous meningoencephalomyelitis in a red kangaroo associated with Angiostrongylus cantonensis infection

Angiostrongylus cantonensis is a zoonotic parasitic helminth that normally resides in the pulmonary arteries and the right ventricle of rats ( Rattus sp.), the definitive host, where it causes little disease. Humans, dogs, opossums, and various zoo animals are “accidental” hosts. Here we report verminous meningoencephalomyelitis caused by A. cantonensis in a 9-mo-old male red kangaroo ( Macropus rufus). The kangaroo was first presented lethargic, recumbent, and hypothermic, with severe muscle wasting. Within 3 wk, he progressed to non-ambulatory paraparesis and died. Gross examination revealed multifocal areas of dark-brown discoloration, malacia, and cavitation in the brain and the spinal cord. Histologically, there were several sections of nematodes surrounded by extensive areas of rarefaction, hemorrhage, spongiosis, neuronal necrosis, and gliosis. Based on size, morphology, and organ location, the nematodes were identified as subadult males and females. Interestingly, an eosinophilic response was largely absent, and the inflammatory response was minimal. A. cantonensis infection had not been reported previously in a red kangaroo in Louisiana or Mississippi, to our knowledge. Our case reaffirms the widespread presence of the helminth in the southeastern United States and indicates that A. cantonensis should be considered as a differential in macropods with neurologic clinical signs in regions where A. cantonensis is now endemic.

Oxidative Stress and Neuronal Injury After Cannabis and Ketamine Administration

Cannabis sativa and ketamine are common substances of abuse causing psychotic events and neurodegeneration. In this study, the effect of pretreatment with Cannabis sativa extract on oxidative stress, inflammatory mediators and brain damage induced by ketamine was investigated. Rats were treated with subcutaneous injections of cannabis extract (10, 20, 30 or 40 mg/kg; expressed as Δ9-THC content) daily for three weeks and then in combination with ketamine (15 mg/kg, intraperitoneally) for another 5 days. Rats were tested for biochemical markers of oxidative stress including malondialdehyde (MDA) reduced glutathione (GSH), and nitric oxide (NO) concentrations in brain. Paraoxonase-1 (PON-1) activity, and levels of the proinflammatory cytokines, interleukin-1β (IL-1β), and tumour necrosis factor-α (TNF-α) in brain were also determined at the end of treatment period. Results indicated that compared with the saline control group, ketamine induced significant elevation in brain MDA and NO, which was accompanied by depletion of GSH and inhibition of PON-1 activity. Ketamine also significantly increased brain IL-1β and TNF-α and induced neuronal necrosis, apoptosis and vacuolation. Cannabis sativa (20-40 mg/kg) pretreated rats showed lower levels of oxidative stress and inflammation and doses of 30 or 40 mg/kg slightly reduced neuronal apoptosis and necrosis. These findings suggest that cannabis constituents do not enhance the neurotoxic effects of ketamine and might partly counteract the effects of ketamine-induced NMDA antagonism by reducing the release of free radicals and inflammatory mediators in brain

Neurotropic Astroviruses in Animals

Astrovirus infections are among the main causes of diarrhea in children, but their significance for animal health has remained underestimated and largely unknown. This is changing due to the increasing amount of newly identified neurotropic astroviruses in cases of nonsuppurative encephalitis and neurological disease in humans, pigs, ruminant species and minks. Neurological cases in ruminants and humans usually occur sporadically and as isolated cases. This contrasts with the situation in pigs and minks, in which diseases associated with neurotropic astroviruses are endemic and occur on the herd level. Affected animals show neurological signs such as mild ataxia to tetraplegia, loss of orientation or trembling, and the outcome is often fatal. Non-suppurative inflammation with perivascular cuffing, gliosis and neuronal necrosis are typical histological lesions of astrovirus encephalitis. Since astroviruses primarily target the gastrointestinal tract, it is assumed that they infect the brain through the circulatory system or retrograde following the nerves. The phylogenetic analysis of neurotropic astroviruses has revealed that they are genetically closely related, suggesting the presence of viral determinants for tissue tropism and neuroinvasion. In this review, we summarize the current knowledge on neurotropic astrovirus infections in animals and propose future research activities.