Author: Bi, Xiaoning ; Khalil, Hany ; Shirokov, Alexander ; Sullivan, Ed ; Wang, Zhijun ; Kamal, Zeechan ; Wang, Yubin ; Luo, Yun Lyna ; Coulter, Greg ; Mehdi, Shujaath ; Baudry, Michel ; Lee, Gary ; Fosnaugh, Kathy ; Lagasca, Dennis ; Bey, Philippe

AbstractOur laboratory has shown that calpain‐2 activation in the brain following acute injury is directly related to neuronal damage and the long‐term functional consequences of the injury, while calpain‐1 activation is generally neuroprotective and calpain‐1 deletion exacerbates neuronal injury. We have also shown that a relatively selective calpain‐2 inhibitor, referred to as C2I, enhanced long‐term potentiation and learning and memory, and provided neuroprotection in the controlled cortical impact (CCI) model of traumatic brain injury (TBI) in mice. Using molecular dynamic simulation and Site Identification by Ligand Competitive Saturation (SILCS) software, we generated about 130 analogs of C2I and tested them in a number of in vitro and in vivo assays. These led to the identification of two interesting compounds, NA‐112 and NA‐184. Further analyses indicated that NA‐184, (S)‐2‐(3‐benzylureido)‐N‐((R,S)‐1‐((3‐chloro‐2‐methoxybenzyl)amino)‐1,2‐dioxopentan‐3‐yl)‐4‐methylpentanamide, selectively and dose‐dependent inhibited calpain‐2 activity without evident inhibition of calpain‐1 at the tested concentrations in mouse brain tissues and human cell lines. Like NA‐112, NA‐184 inhibited TBI‐induced calpain‐2 activation and cell death in mice and rats, both male and females. Pharmacokinetic and pharmacodynamic analyses indicated that NA‐184 exhibited properties, including stability in plasma and liver and blood–brain barrier permeability, that make it a good clinical candidate for the treatment of TBI.

01 Oct 2023·Neurotherapeutics

Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury

Review

Author: Luo, Yun Lyna ; Baudry, Michel ; Bi, Xiaoning

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.

Cell Communication and Signaling

T-type voltage-gated channels, Na+/Ca2+-exchanger, and calpain-2 promote photoreceptor cell death in inherited retinal degeneration

Article

Author: He, Xinyi ; Yang, Qian-Lu ; Seeliger, Mathias W ; Hu, Zhulin ; Yan, Jie ; Paquet-Durand, François ; Yang, Qian-Xi ; Dong, Yujie ; Wang, Lan ; Jiao, Kangwei

AbstractInherited retinal degenerations (IRDs) are a group of untreatable and commonly blinding diseases characterized by progressive photoreceptor loss. IRD pathology has been linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na+- and Ca2+-influx, subsequent activation of voltage-gated Ca2+-channels (VGCC), and further Ca2+ influx. However, a connection between excessive Ca2+ influx and photoreceptor loss has yet to be proven.Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the rd1 mouse model for IRD and wild-type (wt) mice. Differentially expressed genes indicated links to several Ca2+-signalling related pathways. To explore these, rd1 and wt organotypic retinal explant cultures were treated with the intracellular Ca2+-chelator BAPTA-AM or inhibitors of different Ca2+-permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca2+-release-activated channel (CRAC), and Na+/Ca2+ exchanger (NCX). Moreover, we employed the novel compound NA-184 to selectively inhibit the Ca2+-dependent protease calpain-2. Effects on the retinal activity of poly(ADP-ribose) polymerase (PARP), sirtuin-type histone-deacetylase, calpains, as well as on activation of calpain-1, and − 2 were monitored, cell death was assessed via the TUNEL assay.While rd1 photoreceptor cell death was reduced by BAPTA-AM, Ca2+-channel blockers had divergent effects: While inhibition of T-type VGCC and NCX promoted survival, blocking CNGCs and CRACs did not. The treatment-related activity patterns of calpains and PARPs corresponded to the extent of cell death. Remarkably, sirtuin activity and calpain-1 activation were linked to photoreceptor protection, while calpain-2 activity was related to degeneration. In support of this finding, the calpain-2 inhibitor NA-184 protected rd1 photoreceptors.These results suggest that Ca2+ overload in rd1 photoreceptors may be triggered by T-type VGCCs and NCX. High Ca2+-levels likely suppress protective activity of calpain-1 and promote retinal degeneration via activation of calpain-2. Overall, our study details the complexity of Ca2+-signalling in photoreceptors and emphasizes the importance of targeting degenerative processes specifically to achieve a therapeutic benefit for IRDs.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Concussion	Phase 1	US	NeurAegis, Inc.Startup	28 Oct 2021

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