Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat.

Saatman, Kathryn E.; Murai, Hisayuki; Bartus, Raymond T.; Smith, Douglas H.; Hayward, Neil J.; Perri, Brian R.; McIntosh, Tracy K.

doi:10.1073/pnas.93.8.3428

Cited by 214 publications

(143 citation statements)

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“…Bartus and colleagues 6 , who investigated the effect of AK 295 in a model of focal ischemic brain damage, showed that the intra-arterial administration of that molecule protected neurons from ischemia. Saatman and colleagues 36 investigated the efficacy of AK 295 in a murine model of experimentally induced traumatic injury. Those investigators showed that calpain has a role in posttraumatic events.…”

Section: Discussionmentioning

confidence: 99%

“…AK 295, which is considered to be an antiapoptotic agent that counteracts the effects of calpains, has been reported to have a role in the treatment of a variety of pathologic CNS conditions (including trauma and brain ischemia) induced in an experimental setting 6,36 . They showed that AK 295 provided significant neuroprotection of brain tissue and attenuated motor and cognitive deficits.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Although calcium effects are so widespread that it has been difficult to define specific mechanisms, intracellular increase of calcium elicits diverse pathological effects through cell death in cerebral ischemia and other neural insults including glutamate, kainite, maitotoxin, and brain trauma, and neurodegenerative processes such as Alzheimer's disease (2,5,6,(35)(36)(37)(38). A wide range of stimuli eliciting apoptotic cell death acts through elevations in intracellular calcium and activations of calpain.…”

Section: Discussionmentioning

confidence: 99%

Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death

Kim

Hong

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

119

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“…These earlier observations have led to the hypothesis that calpains play an important role in modulating cellular structure in both normal and pathological states. For example, increased calpain activation has been associated with neuronal degeneration caused by traumatic events such as excitotoxicity and hypoxia/ischemia (Kampfl et al, l996a;Yamashima et al, 1996), and various calpain inhibitors such as calpain inhibitor I, calpain inhibitor II, leupeptin, MDL-28 170, and A295 prevented insult-induced neuronal degeneration in both animal (Bartus et al, 1994;Kampfl et al, 1996b;Saatman et al, 1996) and neuronal cell culture models (Brorson et al, 1995; for review, see Wang and Yuen, 1994). In contrast, calpain activity has been shown to play a role in the recovery of neuronal cell structure after cytotoxic insults (Faddis et al, 1997) and is postulated to contribute to neuronal plasticity (Vanderklish et al, 1996) and modification of synaptic function (Dosemeci and Reese, 1995).…”

Section: Discussionmentioning

confidence: 99%

Ceramide Selectively Decreases Tau Levels in Differentiated PC12 Cells Through Modulation of Calpain I

Xie

Johnson

1997

Journal of Neurochemistry

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Ceramide has been recently proposed to be a signal mediator in several important physiological processes including apoptosis, cellular growth, and differentiation. Because the microtubule-associated protein tau plays an important role in the establishment and maintenance of neuronal morphology, the effects of ceramide on tau were examined. Treatment of differentiated P012 cells with the cell-permeable ceramide derivative N-acetylsphingosine (C2) resulted in a significant reduction in tau levels. Significant decreases in tau levels were also observed when the cells were treated with another ceramide derivative, N-hexanoylsphingosine (06). In addition, C2 treatment increased the levels of a calpain-derived spectrin breakdown product but did not alter the levels of two cytoskeletal proteins, a-actin and a-tubulin. Because both tau and spectrin are proteolyzed in vitro by the calcium-activated cysteine protease calpain, the effects of ceramide analogues on the activity of this protease were examined. Treatment of P012 cells with C2 enhanced calcium-stimulated proteolytic activity significantly, as revealed by monitoring the hydrolysis of the membrane-permeable calpain-selective fluorescence probe N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosine-7-amido-4-methylcoumarin. This activity increase was not due to a direct effect of 02 on calpains, because 02 did not alter the activities of purified calpain I or II. In addition, 02 treatment of PC12 cells resulted in a significant increase in the levels of calpain I and, to a lesser extent, the levels of calpastatin (an endogenous calpain inhibitor protein), whereas the levels of calpain II were not changed. Moreover, treatment of the cells with the synthetic calpain-specific inhibitor N-carbobenzoxy-L-leucyl-L-leucyl-L-tyrosine diazomethyl ketone blocked the 02-induced decreases in tau levels. These results indicate that tau levels are regulated in response to a physiological factor and, thus, have implications for ceramidemediated changes in normal and pathological neuronal processes.

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Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat.

Abstract: Marked

Cited by 214 publications

References 52 publications

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

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

Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death

Ceramide Selectively Decreases Tau Levels in Differentiated PC12 Cells Through Modulation of Calpain I

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