Calpain-2 as a therapeutic target for acute neuronal injury

ABSTRACT

Introduction: Calpains represent a family of neutral, calcium-dependent proteases, which modify the function of their target proteins by partial truncation. These proteases have been implicated in numerous cell functions, including cell division, proliferation, migration, and death. In the CNS, where calpain-1 and calpain-2 are the main calpain isoforms, their activation has been linked to synaptic plasticity as well as to neurodegeneration. This review will focus on the role of calpain-2 in acute neuronal injury and discuss the possibility of developing selective calpain-2 inhibitors for therapeutic purposes.

Areas covered: This review covers the literature showing how calpain-2 is implicated in neuronal death in a number of pathological conditions. The possibility of developing new selective calpain-2 inhibitors for treating these conditions is discussed.

Expert opinion: As evidence accumulates that calpain-2 activation participates in acute neuronal injury, there is interest in developing therapeutic approaches using selective calpain-2 inhibitors. Recent data indicate the potential use of such inhibitors in various pathologies associated with acute neuronal death. The possibility of extending the use of such inhibitors to more chronic forms of neurodegeneration is discussed.

KEYWORDS:

• Calpain-2
• neuronal death
• inhibitors
• traumatic brain injury
• acute glaucoma

Article Highlights

• Calpain-2 is neurodegenerative and several downstream signaling pathways lead to neuronal death.

• Calpain-2 activation is delayed and prolonged in two models of acute neuronal injury, acute glaucoma, and TBI.

• In TBI, the extent of cell death is directly related to calpain-2 activation.

• A selective calpain-2 inhibitor provides a highly significant degree of neuroprotection when administered after the injury in both acute glaucoma and TBI.

• A selective calpain-2 inhibitor could be a potential candidate for the treatment of several neurological disorders associated with acute neuronal death.

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Declaration of interest

Y. Wang, X. Bi and M. Baudry are co-founders of NeurAegis, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by grants P01NS045260-01 from NINDS (PI: Dr. C.M. Gall), and grant R21NS057128 from NINDS to M. Baudry, and grant R15MH101703 from NIMH to X. Bi. X. Bi is also supported by funds from the Daljit and Elaine Sarkaria Chair.