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Published on: April 6, 2014
Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury
Michel Baudry1, Yun Lyna Luo2, Xiaoning Bi3
1CDM, Western University of Health Sciences, 309 E. 2nd St, Pomona, CA, 91766, USA. mbaudry@westernu.edu.
Abstract:
While calpains have long been implicated in neurodegeneration, no calpain inhibitor has been developed for the treatment of neurodegeneration. This is partly due to the lack of understanding of the specific functions of most of the 15 members of the calpain family. Work from our laboratory over the last 5-10 years has revealed that calpain-1 and calpain-2, two of the major calpain isoforms in the brain, play opposite roles in both synaptic plasticity/learning and memory and neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering certain forms of synaptic plasticity and for learning some types of information and is neuroprotective. In contrast, calpain-2 activation limits the extent of synaptic plasticity and of learning and is neurodegenerative. These results have been validated with the use of calpain-1 knock-out mice and mice with a selective calpain-2 deletion in excitatory neurons of the forebrain. Through a medicinal chemistry campaign, we have identified a number of selective calpain-2 inhibitors and shown that these inhibitors do facilitate learning of certain tasks and are neuroprotective in a number of animal models of acute neurodegeneration. One of these inhibitors, NA-184, is currently being developed for the treatment of traumatic brain injury, and clinical trials are being planned.
Insights
Calpain-2 inhibition shows promise for treating neurodegenerative diseases by enhancing learning and providing neuroprotection. Selective calpain-2 inhibitors are being developed for conditions like traumatic brain injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Calpains are implicated in neurodegeneration, but specific isoform functions remain unclear.
- Calpain-1 and calpain-2 exhibit opposing roles in synaptic plasticity, learning, and neurodegeneration.
- Understanding these distinct roles is crucial for developing targeted neuroprotective therapies.
Purpose of the Study:
- To investigate the opposing roles of calpain-1 and calpain-2 in brain function.
- To develop selective calpain-2 inhibitors for potential therapeutic applications.
- To evaluate the neuroprotective and cognitive-enhancing effects of calpain-2 inhibitors.
Main Methods:
- Utilized calpain-1 knockout mice and forebrain-specific calpain-2 deletion models.
- Conducted medicinal chemistry campaigns to identify selective calpain-2 inhibitors.
- Assessed inhibitor efficacy in animal models of acute neurodegeneration and learning tasks.
Main Results:
- Calpain-1 activation is essential for synaptic plasticity, learning, and neuroprotection.
- Calpain-2 activation impairs synaptic plasticity, learning, and promotes neurodegeneration.
- Selective calpain-2 inhibitors facilitated learning and demonstrated neuroprotection in preclinical models.
- NA-184, a selective calpain-2 inhibitor, is advancing to clinical trials for traumatic brain injury.
Conclusions:
- Calpain-1 and calpain-2 possess distinct, opposing functions in the brain.
- Targeting calpain-2 with selective inhibitors represents a viable therapeutic strategy for neurodegenerative conditions.
- Further development of calpain-2 inhibitors, such as NA-184, holds significant potential for treating brain injuries and diseases.
