Calpain Inhibition Prevents Ethanol-Induced Alterations in Spinal Motoneurons

Samantaray, Supriti; Patel, Krishna Kumar; Knaryan, Varduhi H.; Thakore, Nakul P.; Roudabush, Stacy; Heissenbuttle, Jenna H.; Becker, Howard C.; Banik, Naren L.

doi:10.1007/s11064-013-1077-1

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…It may be that calpain activation is a downstream effect of many cellular injuries, including disrupted axonal transport that leads to cytoskeletal degradation, DNA fragmentation, apoptosis and ultimately cell death. Therefore, calpain inhibitors may serve a useful approach in neuroprotection in many neurological disorders (Amini et al, 2013;Baudry et al, 2013;Das et al, 2012;Huang and Wang, 2001;Ma et al, 2013;Samantaray et al, 2013aSamantaray et al, , 2013b. In the present study, we sought to explain the role of calpain activation with respect to alterations in TTX-R Na þ channel kinetics in diabetic neuropathy, which can form novel target for drug treatment in diabetic complications.…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

2015

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Section: Discussionmentioning

confidence: 99%

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

2015

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“…Immunoblotting was performed following the described protocol (Samantaray et al, 2007; Samantaray et al, 2013a; Samantaray et al, 2013b). Briefly, dissected tissues (hippocampus, cerebellum, spinal cord) were homogenized in ice-cold homogenizing buffer (50 mM Tris-HCl, pH 7.4; 5 mM EGTA) with freshly added phenylmethylsulfonyl fluoride (1 mM), and protein was estimated using Coomassie plus Protein Assay Reagent (Pierce).…”

Section: Methodsmentioning

confidence: 99%

Chronic intermittent ethanol induced axon and myelin degeneration is attenuated by calpain inhibition

et al. 2015

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Chronic alcohol consumption causes multifaceted damage to the central nervous system (CNS), underlying mechanisms of which are gradually being unraveled. In our previous studies, activation of calpain, a calcium-activated neutral protease has been found to cause detrimental alterations in spinal motor neurons following ethanol (EtOH) exposure in vitro. However, it is not known whether calpain plays a pivotal role in chronic EtOH exposure-induced structural damage to CNS in vivo. To test the possible involvement of calpain in EtOH-associated neurodegenerative mechanisms the present investigation was conducted in a well-established mouse model of alcohol dependence - chronic intermittent EtOH (CIE) exposure and withdrawal. Our studies indicated significant loss of axonal proteins (neurofilament light and heavy, 50-60 %), myelin proteins (myelin basic protein, 20-40 % proteolipid protein, 25 %) and enzyme (2′, 3′-cyclic-nucleotide 3′-phosphodiesterase, 21-55 %) following CIE in multiple regions of brain including hippocampus, corpus callosum, cerebellum, and importantly in spinal cord. These CIE-induced deleterious effects escalated after withdrawal in each CNS region tested. Increased expression and activity of calpain along with enhanced ratio of active calpain to calpastatin (sole endogenous inhibitor) was observed after withdrawal compared to EtOH exposure. Pharmacological inhibition of calpain with calpeptin (25 μg/kg) prior to each EtOH vapor inhalation significantly attenuated damage to axons and myelin as demonstrated by immuno-profiles of axonal and myelin proteins, and Luxol Fast Blue staining. Calpain inhibition significantly protected the ultrastructural integrity of axons and myelin compared to control as confirmed by electron microscopy. Together, these findings confirm CIE exposure and withdrawal induced structural alterations in axons and myelin, predominantly after withdrawal and corroborate calpain inhibition as a potential protective strategy against EtOH associated CNS degeneration.

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“…12.5 µL (12.5 µg total protein) of each sample will be loaded into 4-20% precast gels (Bio-Rad Laboratories, CA, USA) and resolved at 100 V for 1 and 1/2 hrs. Immunoblotting was performed as described in a previous lab publication 47 . The resolved gel was transferred to Immobilon™-polyvinylidene fluoride microporous membranes (Millipore, MA, 9 USA).…”

Section: Western Blot S100βmentioning

confidence: 99%

Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue

Cox

Varma

Barry

et al. 2015

Journal of Neurotrauma

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Persons with spinal cord injury (SCI) are in need of effective therapeutics. Estrogen (E2), as a steroid hormone, is a highly pleiotropic agent; with anti-inflammatory, anti-apoptotic, and neurotrophic properties, it is ideal for use in treatment of patients with SCI. Safety concerns around the use of high doses of E2 have limited clinical application, however. To address these concerns, low doses of E2 (25 μg and 2.5 μg) were focally delivered to the injured spinal cord using nanoparticles. A per-acute model (6 h after injury) was used to assess nanoparticle release of E2 into damaged spinal cord tissue; in addition, E2 was evaluated as a rapid anti-inflammatory. To assess inflammation, 27-plex cytokine/chemokine arrays were conducted in plasma, cerebrospinal fluid (CSF), and spinal cord tissue. A particular focus was placed on IL-6, GRO-KC, and MCP-1 as these have been identified from CSF in human studies as potential biomarkers in SCI. S100β, an additional proposed biomarker, was also assessed in spinal cord tissue only. Tissue concentrations of E2 were double those found in the plasma, indicating focal release. E2 showed rapid anti-inflammatory effects, significantly reducing interleukin (IL)-6, GRO-KC, MCP-1, and S100β in one or all compartments. Numerous additional targets of rapid E2 modulation were identified including: leptin, MIP-1α, IL-4, IL-2, IL-10, IFNγ, tumor necrosis factor-α, etc. These data further elucidate the rapid anti-inflammatory effects E2 exerts in an acute rat SCI model, have identified additional targets of estrogen efficacy, and suggest nanoparticle delivered estrogen may provide a safe and efficacious treatment option in persons with acute SCI.

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Calpain Inhibition Prevents Ethanol-Induced Alterations in Spinal Motoneurons

Cited by 5 publications

References 37 publications

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

Chronic intermittent ethanol induced axon and myelin degeneration is attenuated by calpain inhibition

Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue

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