The Experts below are selected from a list of 5913 Experts worldwide ranked by ideXlab platform
Naren L. Banik - One of the best experts on this subject based on the ideXlab platform.
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cell permeable Calpain Inhibitor sja6017 provides functional protection to spinal motoneurons exposed to mpp
Neurotoxicity Research, 2020Co-Authors: Supriti Samantaray, Mitsuyoshi Azuma, Jun Inoue, Varduhi H. Knaryan, Angelo M Del Re, John J Woodward, Donald C Shields, Swapan K Ray, Naren L. BanikAbstract:Extra-nigral central nervous system sites have been found to be affected in Parkinson’s disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.1 cells differentiated into motoneurons were used as a cell culture model following exposure to Parkinsonian neurotoxicant MPP+. SJA6017, a cell-permeable Calpain Inhibitor, was tested for its neuroprotective efficacy against the neurotoxicant. SJA6017 attenuated MPP+-induced rise in intracellular free Ca2+ and concomitant increases in the active form of Calpain. It also significantly prevented increased levels of proteases and their activities, as shown by reduced levels of 145 kDa Calpain-specific and 120 kDa caspase-3-specific spectrin breakdown products. Exposure to MPP+ elevated the levels of reactive oxygen species in VSC 4.1 motoneurons; this was significantly diminished with SJA6017. The motor proteins in spinal motoneurons, i.e., dynein and kinesin, were also impaired following exposure to MPP+ through Calpain-mediated mechanisms; this process was partially ameliorated by SJA6017 pretreatment. Cytoprotection provided by SJA6017 against MPP+-induced damage to VSC 4.1 motoneurons was confirmed by restoration of membrane potential via whole-cell patch-clamp assay. This study demonstrates that Calpain inhibition is a prospective route for neuroprotection in experimental PD; moreover, Calpain Inhibitor SJA6017 appears to be an effective neuroprotective agent against MPP+-induced damage in spinal motoneurons.
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snj 1945 a Calpain Inhibitor protects sh sy5y cells against mpp and rotenone
Journal of Neurochemistry, 2014Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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effects of a novel orally administered Calpain Inhibitor snj 1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis
Journal of Neurochemistry, 2014Co-Authors: Nicole Trager, Mitsuyoshi Azuma, Jun Inoue, Amena Smith, Gerald C Wallace, Craig Beeson, Azizul Haque, Naren L. BanikAbstract:Multiple sclerosis (MS) pathology is marked by the massive infiltration of myelin-specific T cells into the CNS. Hallmarks of T helper (Th) cells during active disease are pro-inflammatory Th1/Th17 cells that predominate over immunoregulatory Th2/Treg cells. Neurodegeneration, a major factor in progressive MS, is often overlooked when considering drug prescription. Here, we show that oral dosing with SNJ-1945, a novel water-soluble Calpain Inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two pronged effect via anti-inflammation and protection against neurodegeneration. We also show that SNJ-1945 treatment down-regulates Th1/Th17 inflammatory responses, and promotes regulatory T cells (Tregs) and myeloid-derived suppressor cells in vivo, which are known to have the capacity to suppress helper as well as cytotoxic T cell functions. Through analysis of spinal cord samples, we show a reduction in Calpain expression, decreased infiltration of inflammatory cells, and signs of inhibition of neurodegeneration. We also show a marked reduction in neuronal cell death in spinal cord (SC) sections. These results suggest that Calpain inhibition attenuates experimental autoimmune encephalomyelitis pathology by reducing both inflammation and neurodegeneration, and could be used in clinical settings to augment the efficacy of standard immunomodulatory agents used to treat MS. Multiple sclerosis (MS) pathology is marked by inflammation and infiltration of myelin-specific T cells into the central nervous system. Inflammation leads to neurodegeneration in progressive MS which also leads to epitope spreading, feedback looping to more inflammation. Calpain can play a role in both arms of the disease. Here, oral dosing with SNJ-1945, a novel water-soluble Calpain Inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two-pronged effect via anti-inflammation and protection against neurodegeneration.
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SNJ-1945, a Calpain Inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone
Journal of neurochemistry, 2013Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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Calpain Inhibitor attenuated optic nerve damage in acute optic neuritis in rats
Journal of Neurochemistry, 2013Co-Authors: Arabinda Das, Swapan K Ray, Denise Matzelle, Kelly M Guyton, Gerald C Wallace, Amena W Smith, Misty L Mcdowell, Naren L. BanikAbstract:Optic neuritis (ON), which is an acute inflammatory autoimmune demyelinating disease of the central nervous system (CNS), often occurs in multiple sclerosis (MS). ON is an early diagnostic sign in most MS patients caused by damage to the optic nerve leading to visual dysfunction. Various features of both MS and ON can be studied following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in Lewis rats. Inflammation and cell death in the optic nerve, with subsequent damage to the retinal ganglion cells in the retina, are thought to correlate with visual dysfunction. Thus, characterizing the pathophysiological changes that lead to visual dysfunction in EAE animals may help develop novel targets for therapeutic intervention. We treated EAE animals with and without the Calpain Inhibitor calpeptin (CP). Our studies demonstrated that the Ca2+-activated neutral protease Calpain was upregulated in the optic nerve following induction of EAE at the onset of clinical signs (OCS) of the disease, and these changes were attenuated following treatment with CP. These reductions correlated with decreases in inflammation (cytokines, iNOS, COX-2, and NF-κB), and microgliosis (i.e. activated microglia). We observed that Calpain inhibition reduced astrogliosis (reactive astroglia) and expression of aquaporin 4 (AQP4). The balance of Th1/Th2 cytokine production and also expression of the Th1-related CCR5 and CXCR3 chemokine receptors influence many pathological processes and play both causative and protective roles in neuron damage. Our data indicated that CP suppressed cytokine imbalances. Also, Bax:Bcl-2 ratio, production of tBid, PARP-1, expression and activities of Calpain and caspases, and internucleosomal DNA fragmentation were attenuated after treatment with CP. Our results demonstrated that CP decreased demyelination [loss of myelin basic protein (MBP)] and axonal damage [increase in dephosphorylated neurofilament protein (de-NFP)], and also promoted intracellular neuroprotective pathways in optic nerve in EAE rats. Thus, these data suggest that Calpain is involved in inflammatory as well as in neurodegenerative aspects of the disease and may be a promising target for treating ON in EAE and MS.
Mitsuyoshi Azuma - One of the best experts on this subject based on the ideXlab platform.
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cell permeable Calpain Inhibitor sja6017 provides functional protection to spinal motoneurons exposed to mpp
Neurotoxicity Research, 2020Co-Authors: Supriti Samantaray, Mitsuyoshi Azuma, Jun Inoue, Varduhi H. Knaryan, Angelo M Del Re, John J Woodward, Donald C Shields, Swapan K Ray, Naren L. BanikAbstract:Extra-nigral central nervous system sites have been found to be affected in Parkinson’s disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.1 cells differentiated into motoneurons were used as a cell culture model following exposure to Parkinsonian neurotoxicant MPP+. SJA6017, a cell-permeable Calpain Inhibitor, was tested for its neuroprotective efficacy against the neurotoxicant. SJA6017 attenuated MPP+-induced rise in intracellular free Ca2+ and concomitant increases in the active form of Calpain. It also significantly prevented increased levels of proteases and their activities, as shown by reduced levels of 145 kDa Calpain-specific and 120 kDa caspase-3-specific spectrin breakdown products. Exposure to MPP+ elevated the levels of reactive oxygen species in VSC 4.1 motoneurons; this was significantly diminished with SJA6017. The motor proteins in spinal motoneurons, i.e., dynein and kinesin, were also impaired following exposure to MPP+ through Calpain-mediated mechanisms; this process was partially ameliorated by SJA6017 pretreatment. Cytoprotection provided by SJA6017 against MPP+-induced damage to VSC 4.1 motoneurons was confirmed by restoration of membrane potential via whole-cell patch-clamp assay. This study demonstrates that Calpain inhibition is a prospective route for neuroprotection in experimental PD; moreover, Calpain Inhibitor SJA6017 appears to be an effective neuroprotective agent against MPP+-induced damage in spinal motoneurons.
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snj 1945 a Calpain Inhibitor protects sh sy5y cells against mpp and rotenone
Journal of Neurochemistry, 2014Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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effects of a novel orally administered Calpain Inhibitor snj 1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis
Journal of Neurochemistry, 2014Co-Authors: Nicole Trager, Mitsuyoshi Azuma, Jun Inoue, Amena Smith, Gerald C Wallace, Craig Beeson, Azizul Haque, Naren L. BanikAbstract:Multiple sclerosis (MS) pathology is marked by the massive infiltration of myelin-specific T cells into the CNS. Hallmarks of T helper (Th) cells during active disease are pro-inflammatory Th1/Th17 cells that predominate over immunoregulatory Th2/Treg cells. Neurodegeneration, a major factor in progressive MS, is often overlooked when considering drug prescription. Here, we show that oral dosing with SNJ-1945, a novel water-soluble Calpain Inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two pronged effect via anti-inflammation and protection against neurodegeneration. We also show that SNJ-1945 treatment down-regulates Th1/Th17 inflammatory responses, and promotes regulatory T cells (Tregs) and myeloid-derived suppressor cells in vivo, which are known to have the capacity to suppress helper as well as cytotoxic T cell functions. Through analysis of spinal cord samples, we show a reduction in Calpain expression, decreased infiltration of inflammatory cells, and signs of inhibition of neurodegeneration. We also show a marked reduction in neuronal cell death in spinal cord (SC) sections. These results suggest that Calpain inhibition attenuates experimental autoimmune encephalomyelitis pathology by reducing both inflammation and neurodegeneration, and could be used in clinical settings to augment the efficacy of standard immunomodulatory agents used to treat MS. Multiple sclerosis (MS) pathology is marked by inflammation and infiltration of myelin-specific T cells into the central nervous system. Inflammation leads to neurodegeneration in progressive MS which also leads to epitope spreading, feedback looping to more inflammation. Calpain can play a role in both arms of the disease. Here, oral dosing with SNJ-1945, a novel water-soluble Calpain Inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two-pronged effect via anti-inflammation and protection against neurodegeneration.
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SNJ-1945, a Calpain Inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone
Journal of neurochemistry, 2013Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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post natal treatment by a blood brain barrier permeable Calpain Inhibitor snj1945 rescued defective function in lissencephaly
Scientific Reports, 2013Co-Authors: Shiori Toba, Mitsuyoshi Azuma, Yasuhisa Tamura, Kanako Kumamoto, Masami Yamada, Keizo Takao, Satoko Hattori, Tsuyoshi Miyakawa, Yosky Kataoka, Kiyoshi HayasakaAbstract:Toward a therapeutic intervention of lissencephaly, we applied a novel Calpain Inhibitor, SNJ1945. Peri-natal or post-natal treatment with SNJ1945 rescued defective neuronal migration in Lis1+/− mice, impaired behavioral performance and improvement of 18F-FDG uptake. Furthermore, SNJ1945 improved the neural circuit formation and retrograde transport of NFG in Lis1+/− mice. Thus, SNJ1945 is a potential drug for the treatment of human lissencephaly patients.
Jun Inoue - One of the best experts on this subject based on the ideXlab platform.
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cell permeable Calpain Inhibitor sja6017 provides functional protection to spinal motoneurons exposed to mpp
Neurotoxicity Research, 2020Co-Authors: Supriti Samantaray, Mitsuyoshi Azuma, Jun Inoue, Varduhi H. Knaryan, Angelo M Del Re, John J Woodward, Donald C Shields, Swapan K Ray, Naren L. BanikAbstract:Extra-nigral central nervous system sites have been found to be affected in Parkinson’s disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.1 cells differentiated into motoneurons were used as a cell culture model following exposure to Parkinsonian neurotoxicant MPP+. SJA6017, a cell-permeable Calpain Inhibitor, was tested for its neuroprotective efficacy against the neurotoxicant. SJA6017 attenuated MPP+-induced rise in intracellular free Ca2+ and concomitant increases in the active form of Calpain. It also significantly prevented increased levels of proteases and their activities, as shown by reduced levels of 145 kDa Calpain-specific and 120 kDa caspase-3-specific spectrin breakdown products. Exposure to MPP+ elevated the levels of reactive oxygen species in VSC 4.1 motoneurons; this was significantly diminished with SJA6017. The motor proteins in spinal motoneurons, i.e., dynein and kinesin, were also impaired following exposure to MPP+ through Calpain-mediated mechanisms; this process was partially ameliorated by SJA6017 pretreatment. Cytoprotection provided by SJA6017 against MPP+-induced damage to VSC 4.1 motoneurons was confirmed by restoration of membrane potential via whole-cell patch-clamp assay. This study demonstrates that Calpain inhibition is a prospective route for neuroprotection in experimental PD; moreover, Calpain Inhibitor SJA6017 appears to be an effective neuroprotective agent against MPP+-induced damage in spinal motoneurons.
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snj 1945 a Calpain Inhibitor protects sh sy5y cells against mpp and rotenone
Journal of Neurochemistry, 2014Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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effects of a novel orally administered Calpain Inhibitor snj 1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis
Journal of Neurochemistry, 2014Co-Authors: Nicole Trager, Mitsuyoshi Azuma, Jun Inoue, Amena Smith, Gerald C Wallace, Craig Beeson, Azizul Haque, Naren L. BanikAbstract:Multiple sclerosis (MS) pathology is marked by the massive infiltration of myelin-specific T cells into the CNS. Hallmarks of T helper (Th) cells during active disease are pro-inflammatory Th1/Th17 cells that predominate over immunoregulatory Th2/Treg cells. Neurodegeneration, a major factor in progressive MS, is often overlooked when considering drug prescription. Here, we show that oral dosing with SNJ-1945, a novel water-soluble Calpain Inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two pronged effect via anti-inflammation and protection against neurodegeneration. We also show that SNJ-1945 treatment down-regulates Th1/Th17 inflammatory responses, and promotes regulatory T cells (Tregs) and myeloid-derived suppressor cells in vivo, which are known to have the capacity to suppress helper as well as cytotoxic T cell functions. Through analysis of spinal cord samples, we show a reduction in Calpain expression, decreased infiltration of inflammatory cells, and signs of inhibition of neurodegeneration. We also show a marked reduction in neuronal cell death in spinal cord (SC) sections. These results suggest that Calpain inhibition attenuates experimental autoimmune encephalomyelitis pathology by reducing both inflammation and neurodegeneration, and could be used in clinical settings to augment the efficacy of standard immunomodulatory agents used to treat MS. Multiple sclerosis (MS) pathology is marked by inflammation and infiltration of myelin-specific T cells into the central nervous system. Inflammation leads to neurodegeneration in progressive MS which also leads to epitope spreading, feedback looping to more inflammation. Calpain can play a role in both arms of the disease. Here, oral dosing with SNJ-1945, a novel water-soluble Calpain Inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two-pronged effect via anti-inflammation and protection against neurodegeneration.
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SNJ-1945, a Calpain Inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone
Journal of neurochemistry, 2013Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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the novel Calpain Inhibitor sja6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury
Journal of Neurotrauma, 2001Co-Authors: Nancy C Kupina, Rathna Nath, Kevin K. W. Wang, Eric E Bernath, Jun Inoue, Azuma Mitsuyoshi, Powai Yuen, Edward D HallAbstract:A principal mechanism of calcium-mediated neuronal injury is the activation of neutral proteases known as Calpains. Proteolytic substrates for Calpain include receptor and cytoskeletal proteins, signal transduction enzymes and transcription factors. Recently, Calpain Inhibitors have been shown to provide benefit in rat models of focal head injury and focal cerebral ischemia. The present study sought to investigate, in experiment 1, the time course of Calpain-mediated cytoskeletal injury in a mouse model of diffuse head injury by measuring the 150- and 145-kDa α-spectrin breakdown products (SBDP). Secondly, in experiment 2, we examined the effect of early (20 min postinjury) administration of the novel Calpain Inhibitor SJA6017 on functional outcome measured 24 h following injury and its effect on posttraumatic α-spectrin degradation. Lastly, in experiment 3, we examined the effect of delayed (4 or 6 h postinjury) administration of SJA6017 on 24-h postinjury functional outcome. In experiment 1, isoflurane-...
Varduhi H. Knaryan - One of the best experts on this subject based on the ideXlab platform.
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cell permeable Calpain Inhibitor sja6017 provides functional protection to spinal motoneurons exposed to mpp
Neurotoxicity Research, 2020Co-Authors: Supriti Samantaray, Mitsuyoshi Azuma, Jun Inoue, Varduhi H. Knaryan, Angelo M Del Re, John J Woodward, Donald C Shields, Swapan K Ray, Naren L. BanikAbstract:Extra-nigral central nervous system sites have been found to be affected in Parkinson’s disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.1 cells differentiated into motoneurons were used as a cell culture model following exposure to Parkinsonian neurotoxicant MPP+. SJA6017, a cell-permeable Calpain Inhibitor, was tested for its neuroprotective efficacy against the neurotoxicant. SJA6017 attenuated MPP+-induced rise in intracellular free Ca2+ and concomitant increases in the active form of Calpain. It also significantly prevented increased levels of proteases and their activities, as shown by reduced levels of 145 kDa Calpain-specific and 120 kDa caspase-3-specific spectrin breakdown products. Exposure to MPP+ elevated the levels of reactive oxygen species in VSC 4.1 motoneurons; this was significantly diminished with SJA6017. The motor proteins in spinal motoneurons, i.e., dynein and kinesin, were also impaired following exposure to MPP+ through Calpain-mediated mechanisms; this process was partially ameliorated by SJA6017 pretreatment. Cytoprotection provided by SJA6017 against MPP+-induced damage to VSC 4.1 motoneurons was confirmed by restoration of membrane potential via whole-cell patch-clamp assay. This study demonstrates that Calpain inhibition is a prospective route for neuroprotection in experimental PD; moreover, Calpain Inhibitor SJA6017 appears to be an effective neuroprotective agent against MPP+-induced damage in spinal motoneurons.
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snj 1945 a Calpain Inhibitor protects sh sy5y cells against mpp and rotenone
Journal of Neurochemistry, 2014Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
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SNJ-1945, a Calpain Inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone
Journal of neurochemistry, 2013Co-Authors: Varduhi H. Knaryan, Mitsuyoshi Azuma, Jun Inoue, Supriti Samantaray, Sookyoung Park, Naren L. BanikAbstract:Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable Calpain Inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active Calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the Calpain Inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with Calpain Inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that Calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious Calpain Inhibitor in this context.
Marta H. Branquinha - One of the best experts on this subject based on the ideXlab platform.
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Susceptibility of promastigotes and intracellular amastigotes from distinct Leishmania species to the Calpain Inhibitor MDL28170.
Parasitology research, 2018Co-Authors: Pedro Soares De Sousa Araújo, Simone S.c. Oliveira, Claudia M. D’avila-levy, André L.s. Santos, Marta H. BranquinhaAbstract:Despite the available drug options, leishmaniasis treatment remains unsatisfactory. The repurposing of Calpain Inhibitors originally developed for human diseases became an interesting alternative, since Leishmania cells express Calpain-related proteins. The susceptibility of six Leishmania species (L. amazonensis, L. braziliensis, L. major, L. mexicana, L. chagasi, and L. donovani) to the Calpain Inhibitor MDL28170 was determined. Promastigote and intracellular amastigote viability in the presence of MDL28170 was evaluated. MDL28170 was able to reduce promastigote proliferation in a dose-dependent manner for all the parasites. A significant reduction on the general parasite metabolism was detected, as judged by resazurin assay, as well as induced important morphological alterations, including rounding promastigotes and loss of the flagellum. MDL28170 was also able to reduce the number of intracellular amastigotes in RAW macrophages. The susceptibility of both parasite stages (promastigotes and amastigotes) to MDL28170 was similar for all Leishmania species tested. MDL28170 showed a much higher toxicity to Leishmania amastigotes when compared with mammalian macrophages, displaying selectivity index values varying from 13.1 to 39.8. These results suggest that the development of Calpain Inhibitors may represent an interesting alternative in the treatment of leishmaniasis.
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in vitro selection of phytomonas serpens cells resistant to the Calpain Inhibitor mdl28170 alterations in fitness and expression of the major peptidases and efflux pumps
Parasitology, 2017Co-Authors: Simone S.c. Oliveira, André L.s. Santos, Vitor Ennesvidal, Claudia M Davilalevy, Ines C Goncalves, Angela H Lopes, Rubem F S Mennabarreto, Marta H. BranquinhaAbstract:The species Phytomonas serpens is known to express some molecules displaying similarity to those described in trypanosomatids pathogenic to humans, such as peptidases from Trypanosoma cruzi (cruzipain) and Leishmania spp. (gp63). In this work, a population of P. serpens resistant to the Calpain Inhibitor MDL28170 at 70 µ m (MDLR population) was selected by culturing promastigotes in increasing concentrations of the drug. The only relevant ultrastructural difference between wild-type (WT) and MDLR promastigotes was the presence of microvesicles within the flagellar pocket of the latter. MDLR population also showed an increased reactivity to anti-cruzipain antibody as well as a higher papain-like proteolytic activity, while the expression of Calpain-like molecules cross-reactive to anti-Dm-Calpain (from Drosophila melanogaster) antibody and calcium-dependent cysteine peptidase activity were decreased. Gp63-like molecules also presented a diminished expression in MDLR population, which is probably correlated to the reduction in the parasite adhesion to the salivary glands of the insect vector Oncopeltus fasciatus. A lower accumulation of Rhodamine 123 was detected in MDLR cells when compared with the WT population, a phenotype that was reversed when MDLR cells were treated with cyclosporin A and verapamil. Collectively, our results may help in the understanding of the roles of Calpain Inhibitors in trypanosomatids.
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MDL28170, a Calpain Inhibitor, Affects Trypanosoma cruzi Metacyclogenesis, Ultrastructure and Attachment to Rhodnius prolixus Midgut
PloS one, 2011Co-Authors: Vítor Ennes-vidal, Marta H. Branquinha, André L.s. Santos, Rubem F. S. Menna-barreto, Claudia M. D’avila-levyAbstract:Background: Trypanosoma cruzi is the etiological agent of Chagas’ disease. During the parasite life cycle, many molecules are involved in the differentiation process and infectivity. Peptidases are relevant for crucial steps of T. cruzi life cycle; as such, it is conceivable that they may participate in the metacyclogenesis and interaction with the invertebrate host. Methodology/Principal Findings: In this paper, we have investigated the effect of the Calpain Inhibitor MDL28170 on the attachment of T. cruzi epimastigotes to the luminal midgut surface of Rhodnius prolixus, as well as on the metacyclogenesis process and ultrastructure. MDL28170 treatment was capable of significantly reducing the number of bound epimastigotes to the luminal surface midgut of the insect. Once the cross-reactivity of the anti-Dm-Calpain was assessed, it was possible to block Calpain molecules by the antibody, leading to a significant reduction in the capacity of adhesion to the insect guts by T. cruzi. However, the antibodies were unable to interfere in metacyclogenesis, which was impaired by the Calpain Inhibitor presenting a significant reduction in the number of metacyclic trypomastigotes. The Calpain Inhibitor also promoted a direct effect against bloodstream trypomastigotes. Ultrastructural analysis of epimastigotes treated with the Calpain Inhibitor revealed disorganization in the reservosomes, Golgi and plasma membrane disruption. Conclusions/Significance: The presence of Calpain and Calpain-like molecules in a wide range of organisms suggests that these proteins could be necessary for basic cellular functions. Herein, we demonstrated the effects of MDL28170 in crucial steps of the T. cruzi life cycle, such as attachment to the insect midgut and metacyclogenesis, as well as in parasite viability and morphology. Together with our previous findings, these results help to shed some light on the functions of T. cruzi Calpains. Considering the potential roles of these molecules on the interaction with both invertebrate and vertebrate hosts, it is interesting to improve knowledge on these molecules in T. cruzi.
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Effects of the Calpain Inhibitor MDL28170 on the clinically relevant forms of Trypanosoma cruzi in vitro
The Journal of antimicrobial chemotherapy, 2010Co-Authors: Vítor Ennes-vidal, Marta H. Branquinha, André L.s. Santos, Rubem F. S. Menna-barreto, Claudia M. D’avila-levyAbstract:There is a general lack of effective and non-toxic chemotherapeutic agents for treating Chagas' disease. In the present work, we evaluated the in vitro activity of the Calpain Inhibitor MDL28170 against Trypanosoma cruzi relevant clinical forms.
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arrested growth of trypanosoma cruzi by the Calpain Inhibitor mdl28170 and detection of Calpain homologues in epimastigote forms
Parasitology, 2009Co-Authors: Leandro S Sangenito, Fernanda A. Marinho, Vitor Ennesvidal, F F Da Mota, A L S Santos, Claudia M Davilalevy, Marta H. BranquinhaAbstract:In this paper, we aimed to explore the effects of the Calpain Inhibitor III (MDL28170) and to detect Calpain-like molecules (CALPs) in epimastigote forms of Trypanosoma cruzi isolate Dm28c. MDL28170 at 70 microM promoted a powerful reduction in the growth rate after 48 h. The IC50 value was calculated to be 31.7 microM. This Inhibitor promoted an increase in the cellular volume, but not cell lysis, resulting in a trypanostatic effect. T. cruzi CALPs presented a strong cross-reactivity with anti-Drosophila melanogaster Calpain and anti-cytoskeleton-associated protein from Trypanosoma brucei antibodies, and labelling was found mainly intracellularly. Furthermore, an 80 kDa reactive protein was detected by Western blotting assays. No significant cross-reactivity was found with anti-human brain Calpain antibody. The expression of CALPs was decreased in cells kept for long periods in axenic cultures in comparison to a strain recently isolated from mice, as well as in MDL28170-treated cells, the latter being paralleled by an increased expression of cruzipain. Different levels of CALPs expression were also detected in distinct phylogenetic lineages, like Y strain (lineage TcII), Dm28c (lineage TcI) [corrected] and INPA6147 strain (Z3 zymodeme). These results may contribute for the investigation of the functions of CALPs in trypanosomatids.
