Promising use of metformin in treating neurological disorders:biomarker-guided therapies

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Unveiling the Threat: Case Reports of Extra-Pulmonary Tuberculosis among Sanctuary Chimpanzees

Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.

Uncovering Consumer Mindsets Regarding Raw Beverages

Nutritional fads in the health and fitness world are constantly changing. Each new craze has its believers and critics. For the consumer, “what to believe” becomes a topic filled with uncertainty. This paper presents a systematic approach to understanding what consumers believe about the health messaging of “raw beverages”. The paper presents both substantive results from US consumers, as well as demonstrates a general approach by which researchers can more deeply understand the consumer mind with respect to the specifics of health and wellness issues.

Nicotinic acetylcholine signaling is required for motor learning but not for rehabilitation from spinal cord injury

Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel compensatory strategies,rehabilitation focuses on resto ring movements lost to injury.Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning,or if it engages previously trained motor circuits without requiring novel learning remains an open question.In this study,mice we re randomly assigned to receive intrape ritoneal injection with the pan-nicotinic,non-competitive antagonist mecamylamine and the nicotinicα7 subunit selective antagonist methyllycaconitine citrate salt or vehicle(normal saline)prior to motor learning assays,then randomly reassigned after motor learning for rehabilitation study post-injury.Ce rvical spinal co rd dorsal column lesion was used as a model of in complete injury.Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury.Our findings indicate that critical diffe rences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.

Statistical Analysis on Gender Difference in Neural Activity for Spatial Ability Tasks

Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although there was no gender-difference in task performance, we found gender differences in neural activity. Some of the important gender differences that we found are 1) that there are far more joint neuro-activations among the brain regions, co-activations or reverse-activations, in males than in females, 2) that the two types of joint activations were nearly half and half in females while it was mostly co-activations in males, 3) that males tend to have more co-activations in the left hemisphere than expected while females tend to have more between-hemisphere co-activations than expected, and 4) that the left-right pairs of BA's are more highly associated than average for males while they are far less associated than average for females.

通过预处理短暂诱导缺氧适应不能提高脊髓损伤后雪旺细胞移植的存活率

缺氧预处理在多种损伤和疾病模型中具有保护作用,但它是否对移植到脊髓损伤(SCI)部位的细胞有益在很大程度上尚待探索。本研究分析了缺氧相关的预处理是否能保护移植到挫伤的大鼠胸髓中的雪旺细胞(SC)。雪旺细胞在移植前通过暴露于低氧(1%O2)或药物制剂(去铁胺或adaptaquin)诱导缺氧预处理。所有预处理方法均诱导缺氧适应,包括HIF-1α及其靶基因的表达增加。然而这些适应是短暂的,并在移植后24 h内消失。药理学预处理减弱了脊髓氧化应激,并增强了移植血管形成,但它并没有改善移植细胞的存活或感觉/运动功能的恢复。总之,这些实验结果表明,与缺氧相关的预处理在改善脊髓损伤后移植雪旺细胞的细胞存活或功能方面是无效的。本研究还揭示了在细胞移植疗法中由预处理引起的缺氧相关适应的益处并不普遍。

内分泌腺体来源的血管内皮生长因子在子宫内膜异位症在位内膜及裸鼠模型中的特异性表达及意义

目的探讨内分泌腺体来源血管内皮生长因子(endocrine gland-derived vascular endothelial growth factor,EG-VEGF)在子宫内膜及裸鼠模型表达及意义。方法留取异位症(EM组)和非异位症患者(NEM组)子宫内膜各24例,种植于裸鼠盆腹腔,5、15、30d处死,获取异位病灶。RT-PCR和原位杂交检测EG-VEGFmRNA表达。结果RT-PCR:2组各期异位病灶EG-VEGFmRNA表达均强于在位内膜,P<0.05,15d最强,与30d比较,P<0.05。原位杂交:2组在位内膜和异位病灶腺细胞、间质和血管内皮细胞均见EG-VEGFmRNA杂交信号,30天弱于5d及15d病灶。结论在位内膜也表达EG-VEGF,异位病灶EG-VEGF过表达,表达程度与异位内膜细胞活性相关。

Dabrafenib,an inhibitor of RIP3 kinase-dependent necroptosis,reduces ischemic brain injury

Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.

Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy

AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM(n = 11) at baseline and at their transition to T2 DM using Illumina Infinium Human Methylation27 Bead Chip, that enables the query of 27578 individual cytosines at Cp G loci throughout the genome, which are focused on the promoter regions of 14495 genes.RESULTS: There were 694 Cp G sites hypomethylated and 174 Cp G sites hypermethylated in progression from Pre-DM to T2 DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective Cp G sites associated with diverse genes that may reflect differences in Pre-DM compared with T2 DM. In addition, there were Cp G hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.

Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.

New generations of dihydropyridines for treatment of hypertension

Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydropyridine （DHP） CCB, addressing pharmacological mecha- nisms for the clinical efficacy of the third and fourth generations of the DHP CCBs, especially on their possible central mechanisms underlying lowering blood pressure.

Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models

Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.

创伤性脑损伤后蛛网膜下腔出血与长期卒中风险的关系（英文）

BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of traumatic subarachnoid hemorrhage(t SAH)may mediate the effect of TBI on long-term stroke risk,as it has previously been linked to short-term vasospasm and delayed cerebral ischemia.METHODS Using administrative claims data,we conducted a retrospective cohort study of acute care hospitalizations.Patients discharged with a first-recorded diagnosis of t SAH were followed for a primary diagnosis of stroke.They were matched to patients with TBI but not t SAH.Cox proportional hazards modeling was used to assess the association between t SAH and stroke while adjusting for covariates.RESULTS:We identified 40 908 patients with TBI(20 454 patients with t SAH)who were followed for a mean of 4.3+1.8 years.A total of 531 had an ischemic stroke after discharge.There was no significant difference in stroke risk between those with t SAH(1.79%;95%confidence interval[CI]1.54%-2.08%)versus without t SAH(2.12%;95%CI 1.83%-2.44%).The same pattern was found in adjusted analyses even when the group was stratified by age-group or by proxies of TBI severity.CONCLU-SIONS:Our findings do not support a role of t SAH in mediating the association between TBI and protracted stroke risk.Further study is required to elucidate the mechanisms of long-term increased stroke risk after TBI.

Biomarker-guided drug therapy: personalized medicine for treating Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).

The role of motor network reorganization during rehabilitation

There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functional impairments with only a limited capacity for spontaneous recovery.For the return of motor function,such as locomotion or hand and arm dexterity,

Exercise training improves participation in persons with multiple sclerosis:A systematic review and meta-analysis

Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS),the effects of exercise training on participation remain unclear.The objectives of this review were to:(1)characterize systematically the use of outcome measures that capture participation in exercise training studies;(2)quantify the effect of exercise training on participation in persons with MS.Methods A search of 6 electronic databases(CINAHL,SPORTDiscuss,Embase,MEDLINE,Cochrane Central,and Scopus)was conducted to identify controlled and noncontrolled trials involving exercise training and participation in persons with MS.Search strings were built from Medical Subject Headings and CINAHL headings.ICF linking rules were used to identify participation chapters and categories captured.Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials comparing exercise effects to no intervention/usual care.Results We included 49 articles involving controlled and noncontrolled exercise trials in the systematic review of outcome measures.We captured 16 different outcome measures that captured all 9 participation chapters and identified 89 unique participation categories.Across these 16 outcome measures,mobility was the most commonly represented participation chapter,with 108 items.A subsample of 23 randomized controlled trials was included in the meta-analysis.An overall effect of 0.60(standard error=0.12,95%confidence interval:0.36-0.84,z=4.9,p<0.001)was calculated,indicating a moderate,positive effect of exercise training on participation.Conclusion The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS.Exercise training has a positive effect on outcomes that capture participation,providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.

RAFting the rapids of axon regeneration signaling

The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the ac- tivity of cell-intrinsic mechanisms that drive axon growth during development is low- and often further suppressed after an injury - and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be ＂reprogrammed＂ to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.

N-methyl-D-aspartate receptor functions altered by neuronal PTP1B activation in Alzheimer’s disease and schizophrenia models

Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.

The Effect of Ethanol on the Neuronal Subserving of Behavior in the Hippocampus

We have previously shown that both acute and chronic ethanol treatment depresses neural activity, specifically in the cingulate cortex. Minor influences were found in the motor cortex. The acute effect of ethanol in the hippocampus was intermediate to those in the cingulate and motor cortices. In the present study, we concentrate on the chronic effects of ethanol on the hippocampus. We demonstrate how the neuronal activity underlying food-acquisition behavior is modified after chronic ethanol treatment, and how the hippocampus subserves formation of newly-formed alcohol-acquisition behavior. Neuronal activity in CA1 was more sensitive to chronic ethanol than the Dg area. Acute administration of ethanol had a normalizing effect on the chronically-treated animals: their performance and the hippocampal neural activity approached a normal range. The sets of neurons involved in food-acquisition behavior formed before chronic ethanol treatment, and those involved in alcohol-acquisition behavior formed after treatment significantly overlapped supporting the view that the neuronal mechanisms of pre-existing behavior provide the basis for the formation of new behavior. Additionally, we also discovered alcohol-acquisition selective neurons. Assuming that the formation of new neuronal specializations underlies learning, we believe that alcohol-selective neurons are specialized during the formation of alcohol-acquisition behavior. Our data demonstrate several new findings on the effect of acute and chronic ethanol on hippocampus activity, and how the neuronal activity relates to behavior before and after ethanol treatment.

Biomarker Symptom Profiles for Schizophrenia and Schizoaffective Psychosis

Background: Neuroscience can assist clinical understanding and therapy by finding neurobiological markers for mental illness symptoms. Objectives: To quantify biomarkers for schizophrenia and schizoaffective disorder and relate these to discrete symptoms of psychosis. Methods: Within a case-control design with multiple exclusion criteria to exclude organic causes and confounding variables, 67 DSM IV-R diagnosed and 67 control participants from a defined hospital, clinic and community catchment area were investigated for candidate markers. Participants underwent protocol-based diagnostic-checking and symptom rating via Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale, functional-rating scales, biological sample-collection and sensory-processing assessment. Blood and urine samples were analysed for monoamine neurotransmitters, their metabolites, vitamin cofactors and intermediate-substances related to oxidative stress and metabolism of monoamines. Neurocognitive assessment of visual and auditory processing was conducted at both peripheral and central levels. Biomarkers were defined by Receiver Operating Curve (ROC) analysis. Spearman’s analysis explored correlations between discrete symptoms and the biomarkers. Results: Receiver Operating Curve (ROC) analysis identified twenty-one biomarkers: elevated urinary dopamine, noradrenaline, adrenaline and hydroxy pyrroline-2-one as a marker of oxidative stress. Other biomarkers were deficits in vitamins D, B6 and folate, elevation of serum B12 and free serum copper to zinc ratio, along with deficits in dichotic listening, distance vision, visual and auditory speed of processing, visual and auditory working memory and six middle ear acoustic reflex parameters. Discrete symptoms such as delusions, hostility, suicidality and auditory hallucinations were biomarker-defined and symptom biomarker correlations assumed an understandable pattern in terms of the catecholamines and their relationship to biochemistry, brain function and disconnectivity. Conclusions: In the absence of a full diagnosis, biomarker-symptom-signatures inform psychiatry about the structure of psychosis and provide an understandable pattern that points in the direction of a new neurobiological system of symptom-formation and treatment.