Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial.

BACKGROUND: Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, presenting significant challenges in its management. METHODS: A randomized, double-blind, placebo-controlled study involving 15 relapsing-remitting MS patients with MS-induced NPP was conducted to evaluate nabilone combined with gabapentin (GBP). Eligible patients stabilized on GBP (≥1,800 mg/day) with inadequate pain relief were recruited. Nabilone or placebo was titrated over 4 weeks (0.5 mg/week increase) followed by 5-week maintenance of 1 mg oral nabilone (placebo) twice daily. Primary outcomes included two daily patient-reported measures using a 100-mm visual analog scale (VAS), pain intensity (VASpain), and impact of pain on daily activities (VASimpact). Hierarchical regression modeling was conducted on each outcome to determine if within-person pain trajectory differed across study groups, during 63-day follow-up. RESULTS: After adjustment for key patient-level covariates (e.g., age, sex, Expanded Disability Status Scale, duration of MS, baseline pain), a significant group × time(2) interaction term was reported for both the VASpain (P < 0.01) and VASimpact score (P < 0.01), demonstrating the adjusted rate of decrease for both outcomes was statistically greater in nabilone vs placebo study group. No significant difference in attrition rates was noted between treatments. Nabilone was well tolerated, with dizziness/drowsiness most frequently reported. CONCLUSION: Nabilone as an adjunctive to GBP is an effective, well-tolerated combination for MS-induced NPP. The results of this study identify a novel therapeutic combination for use in this population of patients predisposed to tolerability issues that may otherwise prevent effective pain management.

The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis.

Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection.

Examining the evidence: complementary adjunctive therapies for multiple sclerosis.

OBJECTIVE: The purpose of this article is to provide a comprehensive overview of the most frequently encountered non-conventional approaches trialed for use in multiple sclerosis (MS). The efficacy and safety of non-conventional approaches ranging from bee venom therapy (BVT) to an array of vitamins and herbal products were discussed and evaluated. METHODS: Relevant English-language articles were identified through searches of MEDLINE (1990-2006), PubMed (1999-2006), Cochrane (1995-2006) and Toxnet (2000-2006). Classification of available literature was conducted according to the evidence based guidelines established by the American Academy of Neurology (AAN). However, due to the non-conventional nature of these treatment approaches, most available literature was derived from anecdotal reports and suboptimal clinical studies, lacking the rigor of evidence-based practice. RESULTS: There is presently only marginal supportive evidence for BVT in MS treatment. The inability to identify and quantify the active component of BVT combined with the associated risk of anaphylaxis has deterred its widespread use. The most promising evidence comes from prophylactic daily supplementation with vitamin D. Despite beneficial reports regarding non-herbal supplements such as alpha-lipoic acid (ALA), luteolin, evening primrose oil and vitamins such as B12, the lack of evidence does not support their prophylactic use. DISCUSSION: Based on available evidence, the prophylactic use of vitamin D is a viable option as an adjunct to conventional medicine. Although there is a lack of conclusive evidence to support the use of other non-conventional treatments, patients are still opting to trial and bare the risks of these products which are accessible without the intervention of a healthcare professional. Controlled, evidence-based trials are essential for healthcare professionals to competently intervene and recommend these products.

Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses.

AIMS: Oligodendrocytes, especially oligodendrocyte precursor cells, are known to be sensitive to hypoxic and metabolic stresses. Vulnerability of oligodendrocytes is considered a contributing factor to white matter dysfunction. However, little is known about the energy processing characteristics of oligodendrocyte lineage cells under basal and metabolic stress conditions. The aim of this study was to identify the energy requirements and cellular responses of oligodendrocytes at different developmental stages. METHODS: We compared the metabolic stress responses between myelinating oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). Differential regulation of cellular response was also investigated. RESULTS: We found that, following cerebral ischemia, monocarboxylate transporter 1 (MCT1) expression was upregulated in the peri-infarct striatum but not in the cortex of the brain. In vitro ischemia models were used to induce oligodendrocyte stress as well. An increase in MCT1 expression was detected in OPCs after a mild oxygen-glucose deprivation. Double-labeled immunohistochemical analysis revealed that OPCs and OLs responded differently to metabolic stresses and that the susceptibility to metabolic stresses of OPCs and OLs was associated with their distinct expression profiles of MCT1. CONCLUSION: Taken together, this study shows that MCT1 plays a role in the responses of OPCs and OLs to metabolic and ischemic stresses and suggests that redistribution of energy substrates is a determinant in white matter injury.

The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis.

BACKGROUND: Neutralizing antibodies (NAbs) develop in patients receiving interferon beta (IFN-beta) for multiple sclerosis (MS). Debate continues concerning the relevance of NAb development on treatment efficacy. OBJECTIVE: To determine the incidence and clinical importance of NAbs in patients with relapsing-remitting MS (RRMS). METHODS: A comprehensive literature review was conducted using PubMed (accessed from 1983 to June 2005), Cochrane MS Group trials register (accessed June 2005), MEDLINE (accessed 1983 to June 2005), and Toxnet (accessed June 2005) databases. NAb-induced changes in clinical efficacy and disease progression were evaluated according to the clinical guidelines established by the American Academy of Neurology. RESULTS: Currently, there is no standardized assay to comparatively assess NAbs among different treatments. NAbs develop independent of age, sex, disease duration and progression index at the onset of treatment. The occurrence of NAbs varies from 2-45% depending on the treatment initiated. NAb+ patients demonstrate accelerated disease progression as confirmed by an approximate 1-point increase in the Expanded Disability Status Scale score. The odds of relapse during a NAb+ period are between 1.51 and 1.58 (p < 0.03) with the time to first relapse being shortened by an average of 244 days after 12 months of IFN-beta therapy. NAb+ patients experience an approximately four-fold increase (p = 0.009) in the median number of active T2 magnetic resonance imaging (MRI) lesions compared to NAb-negative patients (1.4 vs. 0.3 respectively, p < 0.01). CONCLUSION: The induction of NAbs in IFN-beta treated patients reduce clinical effect and accelerate disease progression.

Inhibitors of enzymes catalyzing modifications to histone lysine residues: structure, function and activity.

Gene expression is partly controlled by epigenetic mechanisms including histone-modifying enzymes. Some diseases are caused by changes in gene expression that can be mitigated by inhibiting histone-modifying enzymes. This review covers the enzyme inhibitors targeting histone lysine modifications. We summarize the enzymatic mechanisms of histone lysine acetylation, deacetylation, methylation and demethylation and discuss the biochemical roles of these modifications in gene expression and in disease. We discuss inhibitors of lysine acetylation, deacetylation, methylation and demethylation defining their structure-activity relationships and their potential mechanisms. We show that there are potentially indiscriminant off-target effects on gene expression even with the use of selective epigenetic enzyme inhibitors.

A treatment algorithm for neuropathic pain.

BACKGROUND: Neuropathic pain is a chronic pain syndrome caused by drug-, disease-, or injury-induced damage or destruction of sensory neurons within the dorsal root ganglia of the peripheral nervous system. Characteristic clinical symptoms include the feeling of pins and needles; burning, shooting, and/or stabbing pain with or without throbbing; and numbness. Neuronal hyperexcitability represents the hallmark cellular mechanism involved in the underlying pathophysiology of neuropathic pain. Although the primary goal is to alleviate pain, clinicians recognize that even the most appropriate treatment strategy may be, at best, only able to reduce pain to a more tolerable level. OBJECTIVE: The purpose of this review is to propose a treatment algorithm for neuropathic pain that health care professionals can logically follow and adapt to the specific needs of each patient. The algorithm is intended to serve as a general guide to assist clinicians in optimizing available therapeutic options. METHODS: A comprehensive review of the literature using the PubMed, MEDLINE, Cochrane, and Toxnet databases was conducted to design and develop a novel treatment algorithm for neuropathic pain that encompasses agents from several drug classes, including antidepressants, antiepileptic drugs, topical antineuralgic agents, narcotics, and analgesics, as well as various treatment options for refractory cases. RESULTS: Any of the agents in the first-line drug classes (tricyclic antidepressants, antiepileptic drugs, topical antineuralgics, analgesics) may be used as a starting point in the treatment of neuropathic pain. If a patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried. When all first-line options have been exhausted, narcotic analgesics or refractory treatment options may provide some benefit. Patients who do not respond to monotherapy with any of the first- or second-line agents may respond to combination therapy or may be candidates for referral to a pain clinic. Because the techniques used at pain clinics tend to be invasive, referrals to these clinics should be reserved for patients who are truly refractory to all forms of pharmacotherapy. CONCLUSIONS: Neuropathic pain continues to be one of the most difficult pain conditions to treat. With the proposed algorithm, clinicians will have a framework from which to design a pain treatment protocol appropriate for each patient. The algorithm will also help streamline referrals to specialized pain clinics, thereby reducing waiting list times for patients who are truly refractory to traditional pharmacotherapy.

Elevated expression of fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) in the dorsal root ganglia and spinal cord in experimental autoimmune encephalomyelitis: implications in multiple sclerosis-induced neuropathic pain.

Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG/SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS.

CXCL1 regulation of oligodendrocyte progenitor cell migration is independent of calcium signaling.

Cell migration is an indispensable aspect of tissue patterning during embryonic development. Oligodendrocytes, the myelinating cells of the central nervous system, migrate significantly during development of the brain. Several growth factors have been identified as being critical regulators of oligodendrocyte progenitor migration, including platelet derived growth factor-A (PDGFA), and fibroblast growth factor-2 (FGF2). Further, the chemokine CXCL1 has been shown to play a critical role in regulating the dispersal of oligodendrocyte progenitors during development, although the mechanisms underlying this regulation are unknown. Previous studies have also shown that calcium flux is required for oligodendrocyte progenitor migration. CXCL1 induces calcium flux in cells; therefore, we hypothesized that CXCL1 inhibition of oligodendrocyte progenitor migration is regulated via changes in intracellular calcium flux. The current study shows that CXCL1 inhibition of oligodendrocyte progenitor migration is independent of calcium signaling. Further, we show that CXCL1 inhibition of oligodendrocyte progenitor migration is specific to PDGFA induced migration. Finally, we show that CXCL1 inhibition of oligodendrocyte progenitor migration is independent of activation of the cell cycle. Our results provide intriguing results relevant to specific aspects of patterning of white matter tracts in the central nervous system, and may further the understanding of tissue remodeling seen during disease-related processes.

Examining the roles of cannabinoids in pain and other therapeutic indications: a review.

IMPORTANCE OF THE FIELD: In recent times, our knowledge of cannabinoids and the endocannabinoid system has greatly advanced. With expanding knowledge, synthetic cannabinoids - including nabilone, dronabinol and a combination of synthetic Delta9-THC and cannabidiol - have been developed and tested for benefit in a variety of therapeutic indications. AREAS COVERED IN THIS REVIEW: The aim of this article is to provide a summative review of the vast amount of clinical trial data now available on these agents. WHAT THE READER WILL GAIN: To locate clinical trials for review, a literature search was performed using PubMed between the dates of 25 May and 30 June 2009. Search parameters were set to isolate only human randomized controlled trials (RCTs) published between 1990 and 2009. Keywords consistently used for each search include: cannabinoids, marijuana, THC, nabilone and dronabinol. Preferential selection was given to the best-designed trials, focusing on placebo-controlled, double-blind RCTs with the largest patient populations, if available. TAKE HOME MESSAGE: As efficacy and tolerability of these agents remain questionable, it is important that cannabinoids not be considered 'first-line' therapies for conditions for which there are more supported and better-tolerated agents. Instead, these agents could be considered in a situation of treatment failure with standard therapies or as adjunctive agents where appropriate.

Bone morphogenetic protein 4 mediates bile duct ligation induced liver fibrosis through activation of Smad1 and ERK1/2 in rat hepatic stellate cells.

Bone morphogenetic proteins (BMPs) are the important cytokine involving in cell differentiation especially in bone morphogenesis. Hepatic stellate cells (HSCs) undergo a trans-differentiation during their activation after liver injury. Although it has been demonstrated that BMP2 and BMP4 significantly increased the abundance of smooth muscle alpha actin (alpha-SMA) in cultured HSCs, the expression of BMPs has not been examined during the activation of HSCs. In current study, we documented the expression of BMP4 in bile duct ligation (BDL) rats and HSCs in culture. We have found that the expression of BMP4 was significantly elevated in the liver of BDL rats. The increase in BMP4 protein showed two peaks during 6 weeks after BDL. The expression and phosphorylation of Smad1, ERK1/2 and p38 were also elevated after BDL. Moreover, there was a gradual elevation of BMP4 mRNA abundance during 24 days' in vitro culture of HSCs. Furthermore, BMP4 stimulated phosphorylation of Smad1 and ERK1/2 in HSCs. In conclusion, BMP4 expression was significantly increased in the liver of BDL rats and HSCs in culture. These findings indicate that BMP4 may mediate HSC activation through activation of Smad1 and ERK1/2.

CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion.

DNA microarray profiling of CD4(+) and CD8(+) cells from non-treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4(+) cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral-mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin-mediated adhesion. Secondly, CYFIP2 knock-down experiments using antisense oligodeoxynucleotides reduced fibronectin-mediated binding in Jurkat and CD4(+) cells. Thirdly, inhibition of Rac-1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin-mediated adhesion in Jurkat and CD4(+) cells. Finally, inhibition of Rac-1 or reduction of CYFIP2 protein decreased fibronectin-mediated adhesion in CD4(+) cells from MS patients to levels similar to controls. These studies suggest that overabundance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.