piperidines and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cachexia; Disease Models, Animal; Mice; Mice, Transgenic; Muscle Weakness; Neurodegenerative Diseases; Phenotype; Piperidines; Superoxide Dismutase; Superoxide Dismutase-1

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease with few therapeutic options. However, the immune system, including natural killer (NK) cells, is linked to ALS progression and may constitute a viable therapeutic ALS target. Tofacitinib is an FDA-approved immunomodulating small molecule which suppresses immune cell function by blocking proinflammatory cytokine signaling. This includes the cytokine IL-15 which is the primary cytokine associated with NK cell function and proliferation. However, the impact of tofacitinib on NK activation and cytotoxicity has not been thoroughly investigated, particularly in ALS. We therefore tested the ability of tofacitinib to suppress cytotoxicity and cytokine production in an NK cell line and in primary NK cells derived from control and ALS participants. We also investigated whether tofacitinib protected ALS neurons from NK cell cytotoxicity. Finally, we conducted a comprehensive pharmacokinetic study of tofacitinib in mice and tested the feasibility of administration formulated in chow. Success was assessed through the impact of tofacitinib on peripheral NK cell levels in mice. We found tofacitinib suppressed IL-15-induced activation as measured by STAT1 phosphorylation, cytotoxicity, pro-inflammatory gene expression, and pro-inflammatory cytokine secretion in both an NK cell line and primary NK cells. Furthermore, tofacitinib protected ALS neurons from NK cell-mediated cytotoxicity. In mice, we found tofacitinib bioavailability was 37% in both male and female mice; using these data we formulated mouse containing low and high doses of tofacitinib and found that the drug suppressed peripheral NK cell levels in a dose-dependent manner. These results demonstrate that tofacitinib can suppress NK cell function and may be a viable therapeutic strategy for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Cytokines; Female; Humans; Killer Cells, Natural; Male; Mice; Neurodegenerative Diseases; Piperidines; Pyrimidines; Signal Transduction

Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.

Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Benzamides; Case-Control Studies; Chymases; Cyclooxygenase 2; Female; Humans; Male; Mast Cells; Mice; Microvessels; Middle Aged; Motor Neurons; Neuroinflammatory Diseases; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Spinal Cord; Stem Cell Factor; Thiazoles; Tryptases

Topics: Amyotrophic Lateral Sclerosis; Benzamides; Clinical Trials as Topic; Humans; Piperidines; Pyridines; Riluzole; Thiazoles

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease. Most patients die within 2 to 5 years of diagnosis. The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease. The economic cost of the disease is not clear, with estimates ranging from about $64,000 per year to $200,000. Two drugs, riluzole and edaravone, are currently FDA approved for the treatment of ALS, and each provides modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.

Topics: Amyotrophic Lateral Sclerosis; Antibodies, Monoclonal, Humanized; Benzamides; Edaravone; Humans; Mesenchymal Stem Cells; Oligonucleotides; Piperidines; Pyridines; Riluzole; Thiazoles

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1

Topics: Amyotrophic Lateral Sclerosis; Animals; Axonal Transport; Cell Death; Cell Survival; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Female; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Motor Neurons; Muscle Cells; Myoblasts, Smooth Muscle; Neuromuscular Junction; Piperidines; Receptors, sigma; Sigma-1 Receptor; Spinal Cord; Superoxide Dismutase-1

RNA dysregulation likely contributes to disease pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. A pathological form of the transactive response (TAR) DNA binding protein (TDP-43) binds to RNA in stress granules and forms membraneless, amyloid-like TDP-43 aggregates in the cytoplasm of ALS motor neurons. In this study, we hypothesized that by targeting the RNA recognition motif (RRM) domains of TDP-43 that confer a pathogenic interaction between TDP-43 and RNA, motor neuron toxicity could be reduced.

Topics: Amyotrophic Lateral Sclerosis; Animals; Base Sequence; Binding Sites; DNA-Binding Proteins; Drosophila melanogaster; Drosophila Proteins; Locomotion; Molecular Docking Simulation; Neuroprotective Agents; Piperidines; Protein Binding; Protein Domains; Pyrazines; RNA; Small Molecule Libraries

Topics: Amyotrophic Lateral Sclerosis; Benzamides; Edaravone; Humans; Muscular Atrophy, Spinal; Neuroprotective Agents; Oligonucleotides; Oligoribonucleotides, Antisense; Piperidines; Pyridines; Thiazoles; Thionucleotides

Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.

Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Benzamides; Cell Degranulation; Disease Models, Animal; Humans; Male; Mast Cells; Motor Neurons; Muscle, Skeletal; Neuromuscular Junction; Neutrophil Infiltration; Neutrophils; Piperidines; Protein Kinase Inhibitors; Pyridines; Rats; Rats, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1; Thiazoles; Treatment Outcome

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined. The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1

Topics: Amyotrophic Lateral Sclerosis; Animals; Arachidonic Acids; Arginase; Benzodioxoles; Brain-Derived Neurotrophic Factor; Cytokines; Disease Models, Animal; Endocannabinoids; Female; Glycerides; Male; Mice; Mice, Transgenic; Molecular Targeted Therapy; Monoacylglycerol Lipases; Neuroglia; Neurons; Piperidines; Primary Cell Culture; Spinal Cord

Topics: Amyotrophic Lateral Sclerosis; Antipyrine; Benzamides; C9orf72 Protein; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Edaravone; Genetic Therapy; Humans; Imidazoles; Mesenchymal Stem Cells; Motor Neurons; Neuroglia; Off-Label Use; Oligoribonucleotides, Antisense; Piperidines; Precision Medicine; Pyrazines; Pyridines; Riluzole; RNAi Therapeutics; Stem Cell Transplantation; Superoxide Dismutase; Thiazoles; United States; United States Food and Drug Administration

Evidence indicates that neuroinflammation contributes to motor neuron degeneration in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease leading to progressive muscular paralysis. However, it remains elusive whether inflammatory cells can interact with degenerating distal motor axons, influencing the progressive denervation of neuromuscular junctions (NMJs). By analyzing the muscle extensor digitorum longus (EDL) following paralysis onset in the SOD1G93A rat model, we have observed a massive infiltration and degranulation of mast cells, starting after paralysis onset and correlating with progressive NMJ denervation. Remarkably, mast cells accumulated around degenerating motor axons and NMJs, and were also associated with macrophages. Mast cell accumulation and degranulation in paralytic EDL muscle was prevented by systemic treatment over 15 days with masitinib, a tyrosine kinase inhibitor currently in clinical trials for ALS exhibiting pharmacological activity affecting mast cells and microglia. Masitinib-induced mast cell reduction resulted in a 35% decrease in NMJ denervation and reduced motor deficits as compared with vehicle-treated rats. Masitinib also normalized macrophage infiltration, as well as regressive changes in Schwann cells and capillary networks observed in advanced paralysis. These findings provide evidence for mast cell contribution to distal axonopathy and paralysis progression in ALS, a mechanism that can be therapeutically targeted by masitinib.

Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Benzamides; Disease Models, Animal; Male; Mast Cells; Muscle, Skeletal; Neuromuscular Diseases; Neuromuscular Junction; Piperidines; Pyridines; Rats; Thiazoles

Neurodegenerative diseases including Alzheimer's disease are complex to tackle because of the complexity of the brain, both in structure and function. Such complexity is reflected by the involvement of various brain regions and multiple pathways in the etiology of neurodegenerative diseases that render single drug target approaches ineffective. Particularly in the area of neurodegeneration, attention has been drawn to repurposing existing drugs with proven efficacy and safety profiles. However, there is a lack of systematic analysis of the brain chemical space to predict the feasibility of repurposing strategies. Using a mechanism-based, drug-target interaction modeling approach, we have identified promising drug candidates for repositioning. Mechanistic cause-and-effect models consolidate relevant prior knowledge on drugs, targets, and pathways from the scientific literature and integrate insights derived from experimental data. We demonstrate the power of this approach by predicting two repositioning candidates for Alzheimer's disease and one for amyotrophic lateral sclerosis.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Computational Biology; Computer Simulation; Cyclosporine; Donepezil; Drug Repositioning; Humans; Indans; Molecular Probes; Neuroprotective Agents; Piperidines; Riluzole; Structure-Activity Relationship

In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.. The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.. We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.. These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Benzamides; Cell Death; Disease Models, Animal; Disease Progression; Encephalitis; Humans; Male; Motor Neurons; Mutation; Neuroglia; Paralysis; Piperidines; Protein Kinase Inhibitors; Pyridines; Rats; Rats, Transgenic; Spinal Cord; Superoxide Dismutase; Thiazoles

We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication.

Topics: Adult; Amyotrophic Lateral Sclerosis; Azathioprine; Benzamides; Biopsy; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Piperidines; Prednisone; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Severity of Illness Index; Thiazoles; Time Factors; Treatment Outcome

A 47-year-old woman with amyotrophic lateral sclerosis was scheduled for total thyroidectomy with cervical node dissection. During anesthetic management by total intravenous anesthesia using remifentanil, propofol, and rocuronium, train-of-four (TOF) monitoring findings were not consistent with clinical signs. Sugammadex successfully reversed shallow respiration.

Topics: Amyotrophic Lateral Sclerosis; Androstanols; Anesthesia, Intravenous; Anesthetics, Intravenous; Female; gamma-Cyclodextrins; Humans; Intraoperative Complications; Lymph Node Excision; Middle Aged; Neuromuscular Nondepolarizing Agents; Piperidines; Propofol; Remifentanil; Respiratory Insufficiency; Rocuronium; Sugammadex; Thyroidectomy

An 82-year-old woman with amyotrophic lateral sclerosis (ALS) with bulbar paralysis, respiratory muscle paralysis, and arteriosclerosis obliterans (ASO) of the lower extremities, underwent uneventful general anesthesia with remifentanil and sevoflurane for bilateral below-knee amputation. Remifentanil is a potent ultra short-acting opioid analgesic drug, undergoes rapid metabolism by non-specific tissue and plasma esterases, and does not accumulate to any clinically important degrees. Furthermore, when remifentanil is used together with propofol during anesthetic induction, successful tracheal intubation can be accomplished without muscle relaxants. These features of remifentanil make it an ideal agent for use in patients with neuromuscular diseases, including ALS, with higher risks of postoperative opioid-induced respiratory depression.

Topics: Aged, 80 and over; Amputation, Surgical; Amyotrophic Lateral Sclerosis; Anesthesia, General; Arteriosclerosis Obliterans; Female; Humans; Leg; Methyl Ethers; Piperidines; Postoperative Complications; Remifentanil; Respiratory Distress Syndrome; Sevoflurane

A 63-year-old woman with amyotrophic lateral sclerosis (ALS) was scheduled for open reduction and internal fixation of the right tibia. Total intravenous anesthesia using propofol and remifentanil without muscle relaxant was selected as the anesthetic method, in order to avoid the possible occurrence of ventilatory depression due to abnormal responses to muscle relaxants and exacerbation of the motor neuron disease. After standard and neuromuscular monitoring devices were applied, anesthesia was induced and maintained with target controlled infusion of propofol and remifentanil in the range of 2.5-5.0 microg x ml(-1) and 2.5-5.0 ng x ml(-1), respectively. To avoid delayed neuromuscular recovery, we did not use any muscle relaxant at all. Intubation was successful and there were no remarkable events during anesthesia, except for three brief hypotensive events; there was no exacerbation of ALS itself during or after the anesthesia. She was discharged on postoperative day 3, without any discomfort.

Topics: Amyotrophic Lateral Sclerosis; Anesthesia, Intravenous; Anesthetics, Intravenous; Female; Fracture Fixation; Humans; Intubation, Intratracheal; Middle Aged; Muscle Relaxants, Central; Piperidines; Propofol; Remifentanil; Tibial Fractures

Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.

Topics: Age Factors; Amyotrophic Lateral Sclerosis; Animals; Cannabinoids; Cell Count; Cell Death; Cell Survival; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Embryo, Mammalian; Humans; L-Lactate Dehydrogenase; Mice; Mice, Transgenic; Motor Neurons; Piperidines; Psychomotor Performance; Pyrazoles; Rimonabant; Spinal Cord; Superoxide Dismutase; tert-Butylhydroperoxide; Time Factors