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Calpain as a Target for Prevention of Neuronal Death in Injuries and Diseases of the Central Nervous System

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Handbook of Neurochemistry and Molecular Neurobiology

Abstract:

Multiple mechanisms are known to contribute to an increase in the intracellular free Ca2+ level. Uncontrolled upregulation of the intracellular free Ca2+ level has been implicated in the pathogenesis of injuries and diseases of the central nervous system (CNS). An increase in the intracellular free Ca2+ level activates the Ca2+-dependent cysteine protease calpain that can mediate neuronal death. Various studies demonstrated that calpain could degrade key cellular substrates so as to impair structural integrity and normal cellular function, leading to both necrotic and apoptotic neuronal death in many CNS disorders. It is now highly recognized from cell culture and animal model studies that calpain has an important role in the mediation of neuronal death in CNS injuries such as ischemic brain injury, spinal cord injury (SCI), and traumatic brain injury (TBI), and also diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), epileptic seizures, Huntington's disease (HD), Parkinson's disease (PD), and multiple sclerosis (MS). In many of these cases, use of calpain inhibitors provided neuroprotection suggesting that calpain could be a potential target for therapeutic interventions. However, currently available calpain inhibitors lack sufficient drug properties that should be addressed adequately before their clinical applications. Importantly, many investigators are now taking interest in developing clinically suitable calpain inhibitors for functional neuroprotection in CNS injuries and diseases.

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Abbreviations

AD:

Alzheimer's disease

ALS:

amyotrophic lateral sclerosis

AMPAR:

α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor

CaBPs:

Ca2+-binding proteins

CANP:

Ca2+-activated neutral protease

CNS:

central nervous system

EAA:

excitatory amino acid

EAE:

experimental allergic encephalomyelitis

ER:

endoplasmic reticulum

HD:

Huntington's disease

iGluR:

ionotropic glutamate receptor

IP3 :

inositol triphosphate

IP3RP3 :

receptors

KAR:

kainate receptor

LGCC:

ligand-gated Ca2+ channels

LGIC:

ligand-gated ion channels

MAP2:

microtubule-associated protein 2

MBP:

myelin basic protein

mGluR:

metabotropic glutamate receptor

MS:

multiple sclerosis

NFP:

neurofilament protein

NMDAR:

N-methyl-d-aspartate receptor

ORP150:

oxygen-regulated protein-150 kDa

PD:

Parkinson's disease

PIP2 :

phosphoinositol biphosphate

PLA2 :

phospholipase A2

ROS:

reactive oxygen species

RyR:

ryanodine receptors

SCI:

spinal cord injury

TBI:

traumatic brain injury

VGCC:

voltage-gated Ca2+ channels

VGIC:

voltage-gated ion channels

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Acknowledgments

This work was supported in part by the R01 grants (CA-91460, NS-31622, NS-38146, NS-41088, NS-45967, and NS-57811) from the National Institutes of Health and also a Spinal Cord Injury Research Foundation grant (SCIRF-0803 and SC9RF-1205) from the state of South Carolina.

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  1. S. K. Ray
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  2. M. K. Guyton
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  3. E. A. Sribnick
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  4. N. L. Banik
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, Newyork, 10962, USA

    Abel Lajtha (Director) (Director)

  2. Department of Neurosciences Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street Suite 309, Charleston, SC 29425, USA

    Naren Banik (Professor) (Professor)

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Ray, S.K., Guyton, M.K., Sribnick, E.A., Banik, N.L. (2007). Calpain as a Target for Prevention of Neuronal Death in Injuries and Diseases of the Central Nervous System. In: Lajtha, A., Banik, N. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30379-6_15

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