Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a disease of the grey matter; however, pathological alterations of the white matter (WM), including axonal loss, axonal demyelination and oligodendrocyte death, have been reported in patients with ALS. The present review examined motor neuron death as the primary cause of ALS and evaluated the associated WM damage that is guided by neuronal-glial interactions. Previous studies have suggested that WM damage may occur prior to the death of motor neurons, and thus may be considered an early indicator for the diagnosis and prognosis of ALS. However, the exact molecular mechanisms underlying early-onset WM damage in ALS have yet to be elucidated. The present review explored the detailed anatomy of WM and identified several pathological mechanisms that may be implicated in WM damage in ALS. In addition, it associated the pathophysiological alterations of WM, which may contribute to motor neuron death in ALS, with similar mechanisms of WM damage that are involved in multiple sclerosis (MS). Furthermore, the early detection of WM damage in ALS, using neuroimaging techniques, may lead to earlier therapeutic intervention, using immunomodulatory treatment strategies similar to those used in relapsing-remitting MS, aimed at delaying WM damage in ALS. Early therapeutic approaches may have the potential to delay motor neuron damage and thus prolong the survival of patients with ALS. The therapeutic interventions that are currently available for ALS are only marginally effective. However, early intervention with immunomodulatory drugs may slow the progression of WM damage in the early stages of ALS, thus delaying motor neuron death and increasing the life expectancy of patients with ALS.

Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE)-induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the myelin repair process by repressing BDNF expression. Using an EAE model of MS, we identify the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF. The expression changes of these key biological targets were then correlated with the temporal changes in neurological disability scores (NDS) over the entire disease course. Our results indicate that MeCP2E1 mRNA levels are elevated in EAE animals relative to naïve control (NC) and active control (AC) animals during all time points of disease progression. Our results suggest that the EAE-induced elevations in MeCP2E1 expression contribute to the repressed BDNF production in the spinal cord (SC). The sub-optimal levels of BDNF result in sustained NDS and associated myelin damage throughout the entire disease course. Conversely, we observed no significant differences in the expression patterns displayed for the MeCP2E2 isoform amongst our experimental groups. However, our results demonstrate that baseline protein expression ratios between the MeCP2E1 versus MeCP2E2 isoforms in the SC are higher than those identified within the dorsal root ganglia (DRG). Thus, the DRG represents a more conducive environment than that of the SC for BDNF production and transport to the CNS to assist in myelin repair. Henceforth, the sub-optimal BDNF levels we report in the SC may arise from the elevated MeCP2E1 vs. MeCP2E2 ratio in the SC that creates a more hostile environment thereby preventing local BDNF production. At the level of transcript, we demonstrate that EAE-induces the pathological enhanced expression of MeCP2E1 that contributes to enhanced NDS during the entire disease course. Thus, the pathological induction of the MeCP2E1 isoform contributes to the disruption of the normal homeostatic signaling equilibrium network that exists between cytokines, neurotrophins and chemokines that regulate the myelin repair process by repressing BDNF. Our research suggests that the elevated ratio of MeCP2E1 relative to MeCP2E2 may be a useful diagnostic marker that clinicians can utilize to determine the degree of neurological disability with associated myelin damage. The elevated MeCP2E1 vs. MeCP2E2 ratios (E1/E2) in the SC prevent BDNF from reaching optimal levels required for myelin repair. Thus, the lower E1/E2 ratios in the DRG, allow the DRG to serve as a weak secondary compensatory mechanism for enhanced production and delivery of BD...

Citrullination of arginine residues is a post-translational modification (PTM) found on myelin basic protein (MBP), which neutralizes MBPs positive charge, and is implicated in myelin damage and multiple sclerosis (MS). Here we identify lysine acetylation as another neutralizing PTM to MBP that may be involved in myelin damage. We quantify changes in lysine and arginine PTMs on MBP derived from mice induced with an experimental autoimmune encephalomyelitis (EAE) model of MS using liquid chromatography tandem mass spectrometry. The changes in PTMs are correlated to changes in neurological disability scoring (NDS), as a marker of myelin damage. We found that lysine acetylation increased by 2-fold on MBP during peak NDS post-EAE induction. We also found that mono- and dimethyl-lysine, as well as asymmetric dimethyl-arginine residues on MBP were elevated at peak EAE disability. These findings suggest that the acetylation and methylation of lysine on MBP are PTMs associated with the neurological disability produced by EAE. Since histone deacetylase (HDAC) inhibitors have been previously shown to improve neurological disability, we also show that treatment with trichostatin A (a HDAC inhibitor) improves the NDS of EAE mice but does not change MBP acetylation.

Background Despite the known safety risks of long-term use of sedative-hypnotic/anxiolytic medications, there has been limited guidance for the safe and effective use of their chronic use in a primary care clinic setting. Understanding the characteristics of patients who receive sedative-hypnotic/anxiolytic medication and the clinical documentation process in primary care is the first step towards understanding the nature of the problem and will help inform future strategies for clinical research and practice. Objectives Characterize patients who received a sedative-hypnotic/anxiolytic prescription in primary care, and (2) gain an understanding of the clinical documentation of sedative-hypnotic/anxiolytic indication and monitoring in electronic medical records (EMR). Methods A random selection of patients who received a prescription for a benzodiazepine or Z-drug hypnotic between January 2014 and August 2016 from four primary care clinics in Winnipeg were included. Data was collected retrospectively using the EMR (Accuro®). Patient variables recorded included sex, age, comorbidities, medications, smoking status, and alcohol status. Treatment variables included drug type, indication, pattern of use, dose, adverse events, psychosocial intervention, tapering attempts, social support, life stressor, and monitoring parameters for sedative-hypnotic use. Demographic and clinical characteristics were described using descriptive statistics. Results Records from a sample of 200 primary care patients prescribed sedative-hypnotic/anxiolytics were analyzed (mean age 55.8 years old, 61.5% ≥ 65 years old, 61.0% female). Long-term chronic use (≥ 1 year) of a sedative-hypnotic/anxiolytic agent was observed in 29.5% of the sample. Zopiclone (30.7%) and lorazepam (28.7%) were the most common agents prescribed. Only 9.5% of patients had documentation of a past tapering attempt of their sedative-hypnotic/anxiolytic. The most common indications for sedative-hypnotic/anxiolytic use recorded were anxiety (33.0%) and sleep (18.0%), but indication was undetermined for 57.0% of patients. Depression (33.5%) and falls (18.5%) were reported by patients after the initiation of these agents. Conclusions A higher proportion of females and users 65 years and older received a prescription for a sedative-hypnotic/anxiolytic, consistent with previous studies on sedative-hypnotic use. We found inconsistencies in the documentation surrounding sedative-hypnotic/anxiolytic use. The indication for their use was unclear in a large number of patients. These findings will help us understand the state of the problem in primary care and inform future strategies for clinical research.