piperidines and Demyelinating-Diseases

With a rapidly evolving complement of advanced targeted therapies in inflammatory bowel disease, additional safety and side effect concerns emerge. It is the purpose of this review to consider various risks with biologic therapies in inflammatory bowel disease and discuss mitigating strategies.. Two recently approved monoclonal antibodies (vedolizumab and ustekinumab) and a Janus kinase inhibitor small molecule (tofacitnib) have introduced a number of novel safety and risk considerations. We review the clinical trial and real-world safety data to date on these agents as well as review new data and considerations with anti-tumor necrosis factor agents. New vaccines for varicella zoster virus, hepatitis B virus, and high-dose influenza have been studied, and we discuss the clinical importance of these findings. Lastly, we make management recommendations in the event of particular side effects or complications. Understanding the risks of new agents in inflammatory bowel disease, potential mitigating strategies, and management considerations is important to achieving and maintaining clinical outcomes in IBD patients.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Demyelinating Diseases; Deprescriptions; Drug Substitution; Gastrointestinal Agents; Humans; Infections; Inflammatory Bowel Diseases; Lymphoma; Melanoma; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk; Risk Assessment; Skin Neoplasms; Tumor Necrosis Factor-alpha; Ustekinumab

We still do not have effective treatment for hippocampal demyelination and memory deficit, the two common comorbidities in multiple sclerosis (MS). This study aimed to assess the therapeutic effect of Piperine (the main alkaloid of black pepper) in an experimental model of demyelination.. Demyelination was induced in male Wistar rats by bilateral injection of lysolecithin (LPC) into the CA1 region of the hippocampus. Piperine (5, 10, 20 mg/kg) was daily injected intraperitoneally three days post LPC injection for ten days. The spatial memory was examined by the Morris water maze task. Demyelination and astrocyte activation were assessed by an immunohistological study. The gene expression analysis of TNF-α, IL1-β, NF-κB, IL-10, Foxp3, iNOS, Nrf2, HO1, MBP, and BDNF was done using qPCR. The total antioxidant capacity of hippocampal tissue was measured using FRAP assay.. Our results showed that piperine improved the memory performance and myelin repair in the hippocampal demyelination model. Piperine inhibited iNOS expression concomitant with enhanced expression levels of Nrf2, HO1 and the total antioxidant capacity in the hippocampal tissue. Piperine treatment significantly reduced the gene expression level of TNF-α, IL1-β, NF-κB, and glial activation in the injured area; however, the mRNA level of IL-10, Foxp3, BDNF and MBP were significantly increased.. We found piperine to be an effective treatment for spatial memory impairment and myelin repair in the hippocampal demyelination model. However, further experimental evidence is needed to investigate the precise mechanisms underlying piperine as a promising therapeutic target in MS patients.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cytokines; Demyelinating Diseases; Gene Expression Regulation; Hippocampus; Lysophosphatidylcholines; Male; Maze Learning; Memory Disorders; Models, Animal; Myelin Sheath; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spatial Memory

Iatrogenic demyelination is a distinct clinical subtype of central nervous system inflammatory disorders. The Janus kinase inhibitor, tofacitinib, is an oral disease-modifying antirheumatic drug that has shown contradictory effects on multiple sclerosis in animal models. In this report, we describe a novel case of reversible multifocal CNS demyelination in a patient with seropositive rheumatoid arthritis on tofacitinib. Although the mechanism is not completely understood, activation of T17 cells by tofacitinib and the subsequent increased production of interleukin-17 could be the cause. Moreover, a link between TNF-α and JAK/STAT pathways has been suggested, which may further explain the occurrence of iatrogenic demyelination in this case.

Topics: Animals; Demyelinating Diseases; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Demyelinating Diseases; Female; Guillain-Barre Syndrome; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Piperidines; Polyradiculoneuropathy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZ-exposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.

Topics: Animals; Astrocytes; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cuprizone; Cyclin-Dependent Kinases; Demyelinating Diseases; Disease Models, Animal; Flavonoids; Gene Expression Regulation; Male; Memory Disorders; Memory, Short-Term; Mice, Inbred C57BL; Microglia; Myelin Sheath; Oligodendroglia; Piperidines; Protein Kinase Inhibitors; Stem Cells; Up-Regulation

The endocannabinoids 2-araquidonoylglycerol (2-AG) and anandamide (AEA) are bioactive lipids crucially involved in the regulation of brain function in basal and pathological conditions. Blockade of endocannabinoid metabolism has emerged as a promising therapeutic strategy for inflammatory diseases of the central nervous system, including myelin disorders such as multiple sclerosis. Nevertheless, the biological actions of endocannabinoid degradation inhibitors in oligodendrocytes and white matter tracts are still ill defined. Here we show that the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 suppressed cell death by mild activation of AMPA receptors in oligodendrocytes in vitro, an effect that was mimicked by MAGL substrate 2-AG and by the second major endocannabinoid AEA, in a concentration-dependent manner, whereas inhibition of the AEA metabolizing enzyme fatty acid amide hydrolase with URB597 was devoid of effect. Pharmacological experiments suggested that oligodendrocyte protection from excitotoxicity resulting from MAGL blockade involved the activation of cannabinoid CB1 receptors and the reduction of AMPA-induced cytosolic calcium overload, mitochondrial membrane depolarization, and production of reactive oxygen species. Administration of JZL184 under a therapeutic regimen decreased clinical severity, prevented demyelination, and reduced inflammation in chronic experimental autoimmune encephalomyelitis. Furthermore, MAGL inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.

Topics: Amidohydrolases; Animals; Benzamides; Benzodioxoles; Cannabinoid Receptor Modulators; Carbamates; Demyelinating Diseases; Monoacylglycerol Lipases; Multiple Sclerosis; Oligodendroglia; Piperidines; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

In stroke, a common cause of neurological disability in adults is that the myelin sheaths are lost through the injury or death of mature oligodendrocytes, and the failure of remyelination may be often due to insufficient proliferation and differentiation of oligodendroglial progenitors. In the current study, we used middle cerebral artery occlusion (MCAO) to induced transient focal cerebral ischemia, and found that WIN55, 212-2 augmented actively proliferating oligodendrocytes measured by CC1 immunoreactive cells within the peri-infarct areas. To establish whether these effects were associated with changes in myelin formation, we analyzed the expression of myelin basic protein (MBP) and myelin ultrastructure. We found that WIN55, 212-2 showed more extensive remyelination than vehicle at 14 days post injection (dpi). The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway may be involved in OPCs differentiation. To determine the regulatory effect of WIN55, 212-2 post-treatment on phospho-ERK 1/2 (p-ERK 1/2) after ischemia/reperfusion, Western blot analysis was performed. We found that WIN55, 212-2 regulated the phosphorylation level of the ERK 1/2 to promote OPCs survival and differentiation. Notably, cannabinoid receptor 1 is coupled to the activation of the ERK cascade. Following rimonabant combined treatment, the effect of WIN55, 212-2 on regulating the phosphorylation level of the ERK 1/2 was reversed, and the effect of accelerated myelin formation was partially inhibited. Together, we first found that WIN55, 212-2 promoted OPCs differentiation and remyelination through regulation of the level of the p-ERK 1/2 via cannabinoid receptor 1.

Topics: Animals; Antimetabolites; Benzoxazines; Blotting, Western; Brain Ischemia; Bromodeoxyuridine; Cannabinoid Receptor Antagonists; Cell Differentiation; Cell Survival; Demyelinating Diseases; Immunohistochemistry; Indicators and Reagents; Male; MAP Kinase Signaling System; Microscopy, Electron; Morpholines; Myelin Basic Protein; Myelin Sheath; Naphthalenes; Oligodendroglia; Phosphorylation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Stroke

Many reports have shown the efficacy of cannabinoid agonists in chronic pain, whereas no report exists concerning the potential effect of cannabinoid antagonists following prolonged treatment. We tested the effects of repeated administration of the selective cannabinoid receptor type 1 (CB1) antagonist, SR141716 (rimonabant), in rats with chronic constriction injury of the sciatic nerve (CCI), an animal model of neuropathic pain. The repeated oral administration of SR141716 (1, 3 and 10 mg/kg, once a day for 1 week, from day 7 after the injury) dose dependently attenuated both thermal and mechanical hyperalgesia. A similar effect was observed in CCI wild-type mice, whereas SR141716 was unable to elicit pain relief in CB1 knockout mice, suggesting CB1 receptors involvement in the SR141716-induced antihyperalgesia. The antihyperalgesic activity of SR141716 was associated with a significant reduction of several pro-inflammatory and pro-nociceptive mediators such as tumor necrosis factor alpha (TNFalpha), prostaglandin-E2 (PGE2), lipoperoxide and nitric oxide (NO) levels. The histological analysis of sciatic nerve sections showed a marked degeneration of myelinated fibers in CCI rats, which was substantially reduced after repeated administration of SR141716. This suggests that the compound may favour myelin repair and consequently promote long-lasting functional recovery. This was confirmed by the maintenance of recovery for at least four weeks after treatment discontinuation. In conclusion, the present findings suggest that SR141716 is effective not only in alleviating neuropathic pain but also in favouring the nerve myelin repair.

Topics: Analysis of Variance; Animals; Blotting, Western; Cannabinoid Receptor Antagonists; Constriction; Demyelinating Diseases; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Lipid Peroxides; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reaction Time; Receptors, Cannabinoid; Rimonabant; Sciatic Nerve; Sciatic Neuropathy; Staining and Labeling; Tumor Necrosis Factor-alpha

Five patients developed a mild to severe polyneuropathy while under treatment with perhexiline maleate, a drug used in long-term treatment of angina pectoris. Recovery took place within a few months after drug withdrawal. We performed qualitative and quantitative light and electron microscopical studies, including teased fiber preparations, in different patients; 16 to 90% of the fibers showed segmental demyelination, an unusual feature in drug-induced neuropathies, and 3 to 20% were undergoing wallerian degeneration. Severe loss of myelinated axons was noted in all 5 patients. In these patients clinical symptoms occurred only when a great number of fibers had already been lost and most of the surviving fibers showed demyelination.

Topics: Aged; Angina Pectoris; Demyelinating Diseases; Female; Humans; Male; Middle Aged; Nerve Fibers; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Ten new cases of perhexiline induced peripheral neuropathies are reported. The authors emphasize the possible association of other neurological disorders: cerebellar symptoms in one case, complex tremor in two other cases, marked decrease of photomotor reflexes in one case and disgeusia in another one. The pharmacocinetic study of 4 cases revealed the presence of a low metabolism of the drug in one of them. Polymorphous inclusions have been seen in Schwann cell and endothelial cell cytoplasm in the three patients with electron microscopic study of the nerves. The pathological study of one case showed the demyelination of spinal cord posterior columns. In another case, who died from hepatic coma, the biochemical study of cerebral lipids revealed the low values of cerebrosides and sulfatides in cerebellum and cerebral white matter.

Topics: Cerebellar Diseases; Coronary Disease; Demyelinating Diseases; Endothelium; Humans; Inclusion Bodies; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Piperidines; Schwann Cells; Spinal Cord Diseases

Topics: Cerebrospinal Fluid Proteins; Demyelinating Diseases; Humans; Perhexiline; Piperidines; Polyradiculopathy