A new mechanism of methylprednisolone and other corticosteroids action demonstrated in vitro: inhibition of a proteinase (calpain) prevents myelin and cytoskeletal protein degradation

Banik, Naren L.; Matzelle, Denise; Terry, Elaine; Hogan, Edward L.

doi:10.1016/s0006-8993(96)01302-9

Cited by 48 publications

(27 citation statements)

References 40 publications

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“…Interestingly, our results reveal that administration of a relatively low dose of methylprednisolone (5 mg/kg, corresponding ~0.8 mg/kg in humans [19]) exacerbates the CMV-induced diaphragm dysfunction, whereas a higher dose (30 mg/kg, corresponding ~5 mg/kg in humans [19]) completely protected the diaphragm against VIDD. The dose-depending effect of corticosteroids are in agreement with previous studies [7,8,31]. Our finding of a negative correlation between calpain activity and either diaphragmatic force production or diaphragm fiber CSA further supports the notion that calpain activation plays an important role in CMV-induced diaphragmatic atrophy and contractile dysfunction.…”

Section: Discussionsupporting

confidence: 92%

“…An in vitro study showed that methylprednisolone was slightly effective at low concentrations while more than 80% of calpain inhibition was observed with high concentrations[7]. This was also confirmed in several in vivo studies where different doses of corticosteroids were administered to animals.…”

Section: Discussionmentioning

confidence: 64%

“…In patients with Duchenne muscular dystrophy, treatment with prednisolone significantly improved muscle strength and this beneficial effect appeared to be associated with an increase in muscle mass probably mediated by inhibition of muscle proteolysis rather than by stimulation of muscle protein synthesis [27]. Inhibition of muscle proteolysis, in particular the calpain system, by corticosteroids has been suggested in several in vitro [7,19,28,29] and in vivo [14,30,31] studies. In addition, treatment with methylprednisolone has been shown to reduce caspase-3 mRNA and protein expression in several animal models [11-13].…”

Section: Discussionmentioning

confidence: 99%

“…In some circumstances, corticosteroids have been shown to inhibit the calpain system [7-10] and the caspase-3 system [11-13]. For calpain, in vitro degradation of neurofilament proteins from rat spinal cord homogenates through calpain activation, was substantially inhibited by corticosteroids in a dose-dependent fashion [7]. Also, in a rat model of ischemia-induced liver injury, pretreatment with prednisolone (10 mg/kg, corresponding ~1.6 mg/kg in humans) abolished calpain activation in the liver [14].…”

Section: Introductionmentioning

confidence: 99%

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Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

et al. 2010

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BackgroundHigh dose of corticosteroids has been previously shown to protect against controlled mechanical ventilation (CMV)-induced diaphragmatic dysfunction while inhibiting calpain activation. Because literature suggests that the calpain inhibiting effect of corticosteroid depends on the dose administered, we determined whether lower doses of corticosteroids would also provide protection of the diaphragm during CMV. This may be important for patients undergoing mechanical ventilation and receiving corticosteroids.MethodsRats were assigned to controls or to 24 hours of CMV while being treated at the start of mechanical ventilation with a single intramuscular administration of either saline, or 5 mg/kg (low MP) or 30 mg/kg (high MP) of methylprednisolone.ResultsDiaphragmatic force was decreased after CMV and this was exacerbated in the low MP group while high MP rescued this diaphragmatic dysfunction. Atrophy was more severe in the low MP group than after CMV while no atrophy was observed in the high MP group. A significant and similar increase in calpain activity was observed in both the low MP and CMV groups whereas the high dose prevented calpain activation. Expression of calpastatin, the endogenous inhibitor of calpain, was decreased in the CMV and low MP groups but its level was preserved to controls in the high MP group. Caspase-3 activity increased in all CMV groups but to a lesser extent in the low and high MP groups. The 20S proteasome activity was increased in CMV only.ConclusionsAdministration of 30 mg/kg methylprednisolone during CMV protected against CMV-induced diaphragm dysfunction while 5 mg/kg was more deleterious. The protective effect is due mainly to an inhibition of the calpain system through preservation of calpastatin levels and to a lesser extent to a caspase-3 inhibition.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

et al. 2010

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“…They concluded that E-64-d may provide functional protection in patients with an SCI. The anti-inflammatory agent methylprednisolone inhibits calpain and provides effective neuroprotection against calpain-mediated apoptosis in rats with an SCI 4,34 .…”

Section: Introductionmentioning

confidence: 99%

Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

et al. 2009

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SummaryBackground. An increase in the level of intracellular calcium activates the calcium-dependent neutral protease calpain, which in turn leads to cellular dysfunction and cell death after an insult to the central nervous system. In this study, we evaluated the effect of a calpain inhibitor, AK 295, on spinal cord structure, neurologic function, and apoptosis after spinal cord injury (SCI) in a murine model.Methods. Thirty albino Wistar rats were divided into 3 groups of 10 each: the sham-operated control group (group 1), the spinal cord trauma group (group 2), and the spinal cord trauma plus AK 295 treatment group (group 3). After having received a combination of ketamine 60 mg/kg and xylazine 9 mg/kg to induce anesthesia, the rats in groups 2 and 3 were subjected to thoracic trauma by the weight drop technique (40 g-cm). One hour after having been subjected to that trauma, the rats in groups 2 and 3 were treated with an intraperitoneal injection of either dimethyl sulfoxide 2 mg/kg or AK 295 2 mg/kg. The effects of the injury and the efficacy of AK 295 were determined by an assessment of the TUNEL technique and the results of examination with a light microscope. The neurologic performance of 5 rats from group 2 and 5 from group 3 was assessed by means of the inclined plane technique and the modified Tarlov's motor grading scale 1, 3, and 5 days after spinal cord trauma.Findings. Light-microscopic examination of spinal cord specimens from group 2 revealed hemorrhage, edema, necrosis, and vascular thrombi 24 hours after trauma. Similar (but less prominent) features were seen in specimens obtained from group 3 rats. Twenty-four hours after injury, the mean apoptotic cell numbers in groups 1 and 2 were zero and 4.57 ± 0.37 cells, respectively. In group 3, the mean apoptotic cell number was 2.30 ± 0.34 cells, a value significantly lower than that in group 2 (P < .05). Five days after trauma, the injured rats in group 2 demonstrated significant motor dysfunction (P < .05). In comparison, the motor scores exhibited by group 3 rats were markedly better (P < .05).Conclusions. AK 295 inhibited apoptosis via calpaindependent pathways and provided neuroprotection and improved neurologic function in a rat model of SCI. To our knowledge, this is the first study to evaluate the use of AK 295, a calpain inhibitor, after SCI. Our data suggest that AK 295 might be a novel therapeutic compound for the neuroprotection of tissue and the recovery of function in patients with a SCI.KEY WORDS: AK 295. Apoptosis. Calpain inhibitor. Secondary damage. Spinal cord trauma.El inhibidor de la calpaina AK 295 inhibe la apoptosis inducida por calpaina y mejora la función neurológica tras traumatismo medular en ratas ResumenIntroducción. Una lesión en el sistema nervioso central origina un incremento en los niveles de calcio intracelular que activa la proteasa neutral calciodependiente calpaina, que a su vez conduce a la producción de disfunción y muerte celular. En este estudio evaluamos el efecto de un inhibidor de la calpaina, AK 295, so...

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Immunobiology of Inherited Muscular Dystrophies

Tidball

Welc

Wehling‐Henricks

2018

Comprehensive Physiology

118

126

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The immune response to acute muscle damage is important for normal repair. However, in chronic diseases such as many muscular dystrophies, the immune response can amplify pathology and play a major role in determining disease severity. Muscular dystrophies are inheritable diseases that vary tremendously in severity, but share the progressive loss of muscle mass and function that can be debilitating and lethal. Mutations in diverse genes cause muscular dystrophy, including genes that encode proteins that maintain membrane strength, participate in membrane repair, or are components of the extracellular matrix or the nuclear envelope. In this article, we explore the hypothesis that an important feature of many muscular dystrophies is an immune response adapted to acute, infrequent muscle damage that is misapplied in the context of chronic injury. We discuss the involvement of the immune system in the most common muscular dystrophy, Duchenne muscular dystrophy, and show that the immune system influences muscle death and fibrosis as disease progresses. We then present information on immune cell function in other muscular dystrophies and show that for many muscular dystrophies, release of cytosolic proteins into the extracellular space may provide an initial signal, leading to an immune response that is typically dominated by macrophages, neutrophils, helper T-lymphocytes, and cytotoxic T-lymphocytes. Although those features are similar in many muscular dystrophies, each muscular dystrophy shows distinguishing features in the magnitude and type of inflammatory response. These differences indicate that there are disease-specific immunomodulatory molecules that determine response to muscle cell damage caused by diverse genetic mutations. © 2018 American Physiological Society. Compr Physiol 8:1313-1356, 2018.

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A new mechanism of methylprednisolone and other corticosteroids action demonstrated in vitro: inhibition of a proteinase (calpain) prevents myelin and cytoskeletal protein degradation

Cited by 48 publications

References 40 publications

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

Immunobiology of Inherited Muscular Dystrophies

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