INTRODUCTION:

Calpain is a calcium (Ca²⁺) dependent cysteine based proteolytic enzyme. Overall, calpain has 15 different subtypes but the majorly two isoformof calpain named as calpain 1and calpain 2 has been studied vigorously. They are ubiquitous and they found in cytosol and mitochondria^1,2. The remaining 13 subtypes of calpain are tissue specific. Interestingly, calpain 1(µ-calpain) and calpain 2 (m-calpain) are named based on the amount of Ca²⁺(micromolar and milimolar respectively) required for their activation within the cells³.Unlikely, other lysosome enzymes calpain has limited role as a proteolytic digestive enzyme over different substrates rather than theyplay an important role in regulatingthe intracellular localization.

Structurally, both the enzymes share a common small structure of around 28 kDa of calpain small subunit 1 (CAPNS1) whereas the large subunit around 80 kDa of calapin 1 and calpain 2 is made up of CAPN1 and CAPN2 gene respectively⁴. The homeostasis of calpain is regulated by concentration of Ca²⁺ available in extracellular matrix. However, the concentration of Ca²⁺in intracellular matrix is inadequate so they compensate the adequate amount of Ca²⁺through Ca²⁺influx or else calcium stored in the endoplasmic reticulum(ER)^5,6. Cells have the tendency to clear all the excess calcium, calpain 1 and 2 gets activated to utilize them effectively but soon they getinactivated once all the calcium has been utilized. Calpain regulate cellular and tissue homeostasis as they involved in cell proliferation, regeneration and apoptosis. However, dysregulation of calpain and calcium results into several pathological conditions. Therefore, calpain 1 and 2 could be consideredas good targets for the detection and therapeutic intervention of several diseases^1,7.

Nowadays, scientists are exploring calpain mediated different molecular and cellular pathways which are associated with the progression of several diseases. Calpain has intervened in different neurodegenerative disorders, cardiovascular diseases, cancer, muscular dystrophy, type-2 diabetes and inflammation etc. Calpain also has an important role in cell proliferation and apoptosis. In this comprehensive review, broadly we discuss signaling pathways are involved in the pathogenesis of certain diseases such as neurodegenerative disorders, cardiovascular diseases and cancer along with the medications evaluated at preclinical and clinical levels.

2. Role of calpains in neurodegenerative disorders:

Calpain regulate several physiological functions and build the structural building blocks for neurons. Over-activation of calpain disturb the neuronal development and further leads to synaptic plasticity and development of neurodegenerative disorders such as Alzheimer’s, Parkinson, stroke, cerebral brain injury, excitotoxicity and Huntington’s disease⁸. Proteins for calpain dependent proteolysis are disease specific such as for Alzheimer’s disease (AD) cyclin dependent kinase 5 (CDK5)⁹, mitogen- activated protein kinase (MAPK), tau kinase etc.^10,11whereas, in Parkinson’s disease α-Synuclein and inflammatory T-cells¹². Alzheimer’s disease (AD) refers as an old age disease with impaired cognitive function and memory loss¹³ as a consequence ofaccumulation of amyloid plaque, tau proteins (extracellular) and neurofibrillary tangles (intracellular) in the brain ^8,14-16. Saitoet. al.¹⁷has reported that the ratio of calpain 1 increased in AD patients when compared with normal subjects. Elevated level of calpain activates neuronal CDK5 and MAPK pathways which lead to^8,18hyperphosphorylation of Tau at specific sites. Eventually, the affinity of Tau protein fragments with microtubules get diminished which force them for self aggregation and form tangles. Similarly, calpain elevates the level of Aβ fragments after cleavage of amyloid precursor protein (APP)¹⁹. Both, tangles and Aβ fragments disrupt the microtubule stability, axonal transportation and structural integrity of neurons ^20,21.

Trinchese F. et al. (2008) showed through their experiment that calpain inhibitors might be useful in amelioration of Alzheimer’s induced memory loss. They harvested hippocampal culture and hippocampal slices from genetically modified APP/PS1 mice for primary cell culture. In these culture or slices, they tested the effect of E64 and BDA-410 in neuronal synapse. E64 is a cysteine protease inhibitor whereas, BDA-410 is a highly calpain specific inhibitor. Surprisingly, both inhibitors restored the normal phosphorylation and distribution of synapsin I protein in neuronal synapse followed by improved working memory and fear associated memory in APP/PS1 mice²².

Medeiros R. et al. (2012), conducted one experiment on genetically altered aged 3xTgAD mice. Age-matched non-transgenic mice were used as normal control. A-705253a calpain inhibitor was given to mice in drinking water at dose of 40 and 80 mg/kg per day followed by behavioral monitoring and some ex-vivo parameters. As a result, they found dose dependent improvement in cognitive impairment, lowered level of Aβ ₄₀ and Aβ₄₂fraction and decreased activation of CDK5²⁰.

Parkinson’s disease (PD) is characterized as a movementdisorder due to imbalance between two neurotransmitters as a result of loss of nigrostriatal dopaminergic neurons²¹. The patients of PD must experience resting tremors, bradykinesia, walking gait and rigidity etc²⁴. There are numerous factors which are responsible to degenerate dopaminergic neurons in substantial nigra, one of them is accumulation of Lewis bodies, a toxic filament made up of α-synuclein²⁵. Lewis bodies are formed when exogenous neurotoxins, oxidative stress and inflammatory T-cells triggers the misfolding and aggregation of α-synuclein²⁶. Additionally, calcium influx due to NMDA receptor activation and excitotoxicity turns calpain into their activated form. These activated calpain accelerate the formation of Lewy body by slicing α-synuclein. Currently, L-DOPA is used as a treatment but in long run they have severe side effects and calpain inhibitors could be a great target for the treatment of PD^8,21.

Zaman. et. al. (2022), performed one study in male Lewis rats. Disease was induced by rotenone (2 mg/kg, SC) daily dosing for four days followed by alternative days for 6 days. The very next day of rotenone first injection, treatment was started by administrating calpeptin, a calpain inhibitor at dose 25µg/kg (i.p.), daily post 1h of rotenone administered. As a result, there was no significant reduction in calpain 1 expression when compared with rotenone control group whereas, the expression of calpain 2 attenuates by calpeptin which was directly correlated with neuronal death. In conclusion, attenuation in calapin 2 expression may be important for neuronal loss in Parkinson’s disease²⁷.

3. Role of calpain in cardiovascular diseases:

Over activation of calpain is not just limited to development of neurodegenerative disorder. It also causes hypertrophy, cell death, cardiac ischemia, myopathy and fibrosis. Interestingly, calpastatin, a natural calpain inhibitors bind to calpain in the ratio of 1:4 and keep calpain inactive^28,29. However, during certain pathological conditions such as oxidative stress, ischemia and toxin exposure leads to imbalance between calpain and calpastatin. As a result, the level of calpastatin does not increase in the same ratio as calpain resulting calpain over activation^30,31. Both isoforms of calpain are present in cytosol and mitochondria which are responsible for the development of some cardiovascular pathological conditions including ischemia, myocardial infarction, coronary artery disease, hypertension, cardiac hypertrophy etc. However, cyto-calpain and mito-calapin are interrelated, indirectly they both accelerates each others activity and synergies the progression of disease³¹. For instance, cyto-calpain interferes with the quality control of mitochondria, mitochondrial induced apoptosis and biogenesis. At each checkpoints different proteins are involved such as Beclin 1³², B-cell lymphoma 2 (Bcl2)^33,34 and PGC-1α³⁵ respectively. These proteins are the substrate of calpain, so cyto-calpain digest these proteins as a result the subsequent pathway of quality check get demolished, and it elevates the mitochondrial apoptosis process leads to heart disease. Similarly, myto-calpain interfere with mitochondrial metabolism as it cleavage a protein called NADH:ubiquinone oxidoreductase core subunit S7 (NDUFS7)³⁶. NDUFS7 is a crucial subunit of complex 1 electron chain reaction (ETC) involved in mitochondrial metabolism. Based on these pathways calpain inhibitor may be useful for amelioration of heart disease. Few studies have been done in the past which proves calpain 1 and calpain 2 are involved in mitochondrial dysfunction as a result heart becomes unhealthy.

Ling et. al. conducted one experiment in genetically modified mice in which CPNS1 gene was deleted whereas, wild type (WT) mice were used as a normal control. The hearts of mice were isolated and under physiological condition, hearts underwent for 25 min of ischemia followed by 30 min of reperfusion. When compared the results at different aspects it was concluded that mitochondrial function and oxidative phosphorylation were improved in CPNS1 deletion mice as compare to WT mice whereas, the level of H₂O₂was decreased. This study clearly indicates calpain 1involved in the progression of heart disease in ischemic condition³⁷.

In another study by Yihui et. al., they develop three different types of chronic heart failure in C57/BL and double transgenic mice. After induction mice were administered MDL-28170 at 10 mg/kg daily (IP), whereas, vehicle group received DMSO in saline. Mice were euthanized at different time points post surgery for further assays. As a result, it was very clear that down regulated JP2 and calpain promotes heart failure. Once calpain inhibitor (MDL-28170) was given to duel transgenic model there was an improvement in JP2 expression followed by T-tubule remodeling. These data revels that calpain inhibitor may be beneficial for heart disease³⁸.

Letavernier et. al. demonstrated role of calpain/calpastatin axis in Ang II induced hypertension. In this study they used calpastatin transgenic mice (CalpTG) and wild type as a normal control. Both groups were administered Ang II at 1.8 µg/kg per min as an infusion for 4 weeks. Systolic BP was measured for all the animals twice in a week through tail cuff. Further, different organs were harvested for further analysis. As a result, systolic BP was almost same for both the groups but Ang II mediated hypertrophy in left ventricle was more in transgenic mice. It was evident that despite of unchanged blood pressure the heart remains protected ³⁹.

4. Role of calpain in cancer:

Cancer is characterized as an uncontrolled growth of cells which metastasized to other organs ⁴⁰. Recent studies suggest that calpain could be a new therapeutic target as they are involved in progression of cancer such as metastasis and tumor genesis. The biggest challenge while targeting calpain for the treatment is different cancers is highly substrate specific. Keeping this in mind it is utmost necessary to do in-vivo validation for specific substrate identification ^{41, 42}. There are several substrates which involved in the cell survival and apoptosis ⁴³. For cell survival, calpain cleaves IκBα, an inhibitor of NF-κB resulting in cell growth ⁴⁴ whereas cleavage of p53 ameliorates cell apoptosis ⁴⁵.

Table: 1 List of different experiments performed in different cancer models by targeting calpain

Types of Cancer	Model	Drug/gene/enzyme	Targeted proteins	Results	References
Ovarian cancer	Human ovarian cancer cells	calpastatin	p53 associated parkin-like protein	inhibits apoptosis	45
Breast cancer	HER2+ and TNBC cell lines	calpain knockdown and 17AAG (chaperone HSP90 inhibitor)	chaperone HSP90	attenuate tumor growth and metastasis	50
Multiple cancer	Colon cancer cells	calpain	cytoplasmic Myc	formation of Myc-nick leads to drug resistance apoptosis	51
Breast cancer	AC2M2 mouse mammary carcinoma cell line	calpain 2 knockdown	Akt, FoxO3a , p27^Kip1	Tumor suppression	52
Head and neck cancer, breast cancer	breast and HN-SCCs cell line	amoeboid variants	HIF-1	restoration of talin-1 & b1 integrin integrity	53
Ovarian cancer	IHOSE and SKOV-3 cells	Tunicamycin and calpeptin	CAPN-1/2	Inhibition of calpain varies in different cell lines	54
Gastric cancer	MKN45 and BALB/c nude mice	Honokiol	calpain 2 mediated GRP94	reduced GRP94 expression and tumor growth	55

Contrary, different caspase of cysteine protease family promotes apoptosis such as caspase-7, 10 and 12 ⁴⁶another protein Bcl2⁴⁷ release cytochrome c after proteolysis^48,49. These pathways may lead to calpain induced cancer therapies. Several researches works on calpain inhibitors to alter the process of calpain induced cell survival and apoptosis as mentioned in Table 1.

5. CONCLUSION:

Over activation of calapin results into activation of many pathways which are not likely meant for homeostasis of physiology. This leads to development of different pathological conditions such as neuronal disorders, ischemic heart, cataract, prostate cancer and diabetes mellitus etc.Despite of having lots of conventional medications for the treatment of different diseases there is still need of exploration of calapinas an emerging target. It may synergize the treatment through combination therapies, even it could be helpful for the treatment of comorbid conditions. Specific proteins are involved in different medical conditions which make them unique in terms of pathways. This is the reason that we need to do vigorous research on specific calpain inhibitors for a particular disease. Till date we don’t have many calpain inhibitors in clinical phase. May be calpain become a universal target for the treatment.

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Received on 06.10.2023 Modified on 05.12.2023

Res. J. Pharmacology and Pharmacodynamics.2024; 16(1):25-29.

DOI: 10.52711/2321-5836.2024.00005