Aging-Exacerbated Acute Axon and Myelin Injury Is Associated with Microglia-Derived Reactive Oxygen Species and Is Alleviated by the Generic Medication Indapamide.

Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of Cybb, the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female Cx3cr1CreER/+:Rosa26tdTom/+ mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated NADPH oxidase generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia NADPH oxidase activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide.SIGNIFICANCE STATEMENT Age is associated with an increased risk for the development of several neurologic conditions including progressive multiple sclerosis, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through NADPH oxidase in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive multiple sclerosis.

An overview of the adverse effects of cannabis use for Canadian physicians.

PURPOSE: Cannabis is the most widely used illicit substance and one of the most commonly used psychoactive substances in the world, preceded only by alcohol, tobacco and caffeine. Recent changes in legislation regarding cannabis use in Canada and potential upcoming changes worldwide may have a further impact on the prevalence of cannabis use. Thus, it is critical to understand the risks and potential adverse health effects of acute and long-term cannabis use. Current literature is lacking in many areas surrounding cannabis use, and for the most part is unable to provide clear associations once confounding variables are considered. Here we provide a general overview of the history of cannabis, the physical and mental health consequences, and the risks to specific groups. SOURCE: A scoping search of published articles in PubMed from the start date (1946) until 2018. PRINCIPAL FINDING: Current evidence supports an association between cannabis use and mild respiratory and cardiac effects, but no clear increased risk of cancer. Psychiatric disorders, including schizophrenia and anxiety, show associations with cannabis use; however, a causal effect of cannabis use is unclear. While no evidence for increased risk in pregnancy has been found, risk is still undetermined. Youth may be at a greater risk as earlier initiation of use increases the risk of adverse health effects. CONCLUSION: Overall, evidence for direct and long-term adverse effects of cannabis use is minimal and additional longitudinal studies will be required to better delineate unidentified effects.

Proceedings from the 8th Annual University of Calgary Leaders in Medicine Research Symposium.

On November 14, 2016, the Leaders in Medicine (LIM) program at the Cumming School of Medicine, University of Calgary hosted its 8th Annual Research Symposium. Professor Stephen Sawcer, Professor of Neurological Genetics at the University of Cambridge and an Honorary Consultant Neurologist at Addenbrooke's Hospital, was the keynote speaker and presented a lecture entitled, "Multiple sclerosis genetics - prospects and pitfalls". This was not only a cutting edge address on genetics but also a thoughtful overview on Dr. Sawcer's career and career choices. We were extremely grateful for the opportunity to have Dr. Sawcer participate in our annual symposium.

Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy.

For decades lysophosphatidylcholine (LPC, lysolecithin) has been used to induce demyelination, without a clear understanding of its mechanisms. LPC is an endogenous lysophospholipid so it may cause demyelination in certain diseases. We investigated whether known receptor systems, inflammation or nonspecific lipid disruption mediates LPC-demyelination in mice. We found that LPC nonspecifically disrupted myelin lipids. LPC integrated into cellular membranes and rapidly induced cell membrane permeability; in mice, LPC injury was phenocopied by other lipid disrupting agents. Interestingly, following its injection into white matter, LPC was cleared within 24 hr but by five days there was an elevation of endogenous LPC that was not associated with damage. This elevation of LPC in the absence of injury raises the possibility that the brain has mechanisms to buffer LPC. In support, LPC injury in culture was significantly ameliorated by albumin buffering. These results shed light on the mechanisms of LPC injury and homeostasis.

Plaque Characteristics on CT Angiography Do Not Improve the Ability to Predict Hemodynamic Instability During and After Carotid Angioplasty and Stenting.

BACKGROUND: Hemodynamic instability is commonly seen during carotid angioplasty and stenting. Although prophylactic treatment with anticholinergics is beneficial, selected use in high-risk patients is desirable. This study examines whether plaque characteristics on computed tomography angiography in addition to demographic factors improve predictive capability. METHODS: We retrospectively collected information from 298 carotid angioplasty procedures between January 2013 and December 2018. Nine individuals were excluded due to a previous ipsilateral endarterectomy. Our primary outcome was a decrease of 20% or more in heart rate or blood pressure at angioplasty. Data were analyzed using χ2 tests and regression statistics. RESULTS: Of the 289 patients included for analysis, 57 had intraoperative instability and 26 had postoperative instability. Radiologist interpretation was found to have a risk ratio of 1.63 (95% confidence interval: 1.00-2.65) for intraoperative instability (P=0.080). Intraoperative instability was significantly associated with subsequent postoperative instability (P=0.005). Our regression model included previous endarterectomy and diabetes as predictive factors with a sensitivity of 11.3% and a specificity of 100.0%. Anticholinergic usage was associated with hypotension without coexisting bradycardia with a risk ratio of 2.36 (95% confidence interval: 1.06-5.26; P=0.047). CONCLUSIONS: Individuals without a previous contralateral endarterectomy and/or history of diabetes are at lower risk of hemodynamic instability. The addition of computed tomography angiographic variables does not improve this prediction. Future prospective, randomized work is required to improve our ability to identify and treat individuals at high risk of instability during carotid angioplasty and stenting.

Multimodal Enhancement of Remyelination by Exercise with a Pivotal Role for Oligodendroglial PGC1α.

Remyelination is a multistep regenerative process that results in the reformation of myelin sheaths around demyelinated axons and is a critical therapeutic target. Here we show that immediate access to a running wheel following toxin-induced demyelination in mice enhances oligodendrogenesis, the rate of remyelination, and the proportion of remyelinated axons. RNA sequencing suggests broad activation of pro-remyelination pathways including phagocytosis by exercise and highlights peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α) activation. By immunohistochemistry and cell type-specific conditional deletion, we confirmed PGC1α within oligodendrocytes as a transiently expressed factor required for the rate of myelin thickening by exercise. We validated the exercise-enhanced clearance of inhibitory lipid debris from lesions. Finally, exercise works in parallel with the remyelinating medication clemastine to produce complete remyelination of lesions. Our study demonstrates physical activity as an integrative means to enhance remyelination and details a multimodal mechanism including the pivotal PGC1α-dependent enhancement of myelin thickness.

Activity-Dependent and Experience-Driven Myelination Provide New Directions for the Management of Multiple Sclerosis.

Despite an appreciation of the importance of myelination and the consequences of pathological demyelination, the fundamental mechanisms regulating myelination are only now being resolved. Neuronal activity has long been considered a plausible regulatory signal for myelination. However, controversy surrounding its dispensability in certain contexts and the difficulty in determining to what degree it influences myelination has limited its widespread acceptance. Recent studies have shed new light on the role of neuronal activity in regulating oligodendrogenesis and myelination. Further, the dynamics of myelin in adulthood and the association between skilled learning and myelination have become increasingly well characterized. These advances present new considerations for the management of multiple sclerosis and open up new approaches to facilitate remyelination following pathological demyelination.

An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination.

Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Experimental demyelination and remyelination of murine spinal cord by focal injection of lysolecithin.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system characterized by plaque formation containing lost oligodendrocytes, myelin, axons, and neurons. Remyelination is an endogenous repair mechanism whereby new myelin is produced subsequent to proliferation, recruitment, and differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes, and is necessary to protect axons from further damage. Currently, all therapeutics for the treatment of multiple sclerosis target the aberrant immune component of the disease, which reduce inflammatory relapses but do not prevent progression to irreversible neurological decline. It is therefore imperative that remyelination-promoting strategies be developed which may delay disease progression and perhaps reverse neurological symptoms. Several animal models of demyelination exist, including experimental autoimmune encephalomyelitis and curprizone; however, there are limitations in their use for studying remyelination. A more robust approach is the focal injection of toxins into the central nervous system, including the detergent lysolecithin into the spinal cord white matter of rodents. In this protocol, we demonstrate that the surgical procedure involved in injecting lysolecithin into the ventral white matter of mice is fast, cost-effective, and requires no additional materials than those commercially available. This procedure is important not only for studying the normal events involved in the remyelination process, but also as a pre-clinical tool for screening candidate remyelination-promoting therapeutics.