calpain and Nervous-System-Diseases

Cannabidiol (CBD) is one of the most abundant components of Cannabis and has long been used in Cannabis-based preparations. Recently, CBD has become a promising pharmacological agent because of its beneficial properties in the pathophysiology of several diseases. Although CBD is a kind of cannabinoid and acts on cannabinoid receptors (CB1 and CB2), molecular targets involved in diverse therapeutic properties of CBD have not been identified because CBD also interacts with other molecular targets. Considering that CBD alters the intracellular calcium level by which calpain activity is controlled, and both CBD and calpain are associated with various diseases related to calcium signaling, including neurological disorders, this review provides an overview of calpain and calcium signaling as possible molecular targets of CBD. As calpain is known to play an important role in the pathophysiology of neurological disease, a deeper understanding of its relationship with CBD will be meaningful. To understand the role of CBD as a calpain regulator, in silico structural analysis on the binding mode of CBD with calpain was performed.

Topics: Calcium, Dietary; Calpain; Cannabidiol; Cannabinoids; Cannabis; Humans; Nervous System Diseases; Receptors, Cannabinoid

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.

Topics: Acute Disease; Animals; Calpain; Drug Design; Humans; Nervous System Diseases; Neurodegenerative Diseases; Neuronal Plasticity; Neurons

Topics: Animals; Calpain; Humans; Nervous System Diseases; Organophosphate Poisoning

The number of mammalian calpain protease family members has grown as many as 15 till recent count. Although initially described as a cytosolic protease, calpains have now been found in almost all subcellular locations i.e., from mitochondria to endoplasmic reticulum and from caveolae to Golgi bodies. Importantly, some calpains do not possess the 28 kDa regulatory subunit and have only the 80 kDa catalytic subunit. In some instances, the 80 kDa subunit by itself confers the calpain proteolytic activity. Calpains have been shown to be involved in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. Recent studies have linked calpain deficiencies or it's over production with a variety of diseases, such as muscular dystrophies, gastropathy, diabetes, Alzheimer's and Parkinson's diseases, atherosclerosis and pulmonary hypertension. Herein, we present a brief overview on some implications of calpains on human health and some diseases.

Topics: Animals; Brain Diseases; Calpain; Cell Adhesion; Cytoskeleton; Humans; Nervous System Diseases; Reperfusion Injury

Proteolysis by calpain is a unique posttranslational modification that can change integrity, localization, and activity of endogenous proteins. Two ubiquitous calpains, mu-calpain and m-calpain, are highly expressed in the central nervous system, and calpain substrates such as membrane receptors, postsynaptic density proteins, kinases, and phosphatases are localized to the synaptic compartments of neurons. By selective cleavage of synaptically localized molecules, calpains may play pivotal roles in the regulation of synaptic processes not only in physiological states but also during various pathological conditions. Activation of calpains during sustained synaptic activity is crucial for Ca2+-dependent neuronal functions, such as neurotransmitter release, synaptic plasticity, vesicular trafficking, and structural stabilization. Overactivation of calpain following dysregulation of Ca2+ homeostasis can lead to neuronal damage in response to events such as epilepsy, stroke, and brain trauma. Calpain may also provide a neuroprotective effect from axotomy and some forms of glutamate receptor overactivation. This article focuses on recent findings on the role of calpain-mediated proteolytic processes in potentially regulating synaptic substrates in physiological and pathophysiological events in the nervous system.

Topics: Animals; Calcium Channels, L-Type; Calcium-Calmodulin-Dependent Protein Kinases; Calpain; Cyclin-Dependent Kinase 5; Humans; Inositol 1,4,5-Trisphosphate Receptors; Nerve Tissue Proteins; Nervous System Diseases; Neuronal Plasticity; Protein Isoforms; Receptors, N-Methyl-D-Aspartate; Sodium-Calcium Exchanger; Synapses; Synaptic Transmission

Caspases are a family of cysteine proteases that are expressed as inactive zymogens and undergo proteolytic maturation in a sequential manner in which initiator caspases cleave and activate the effector caspases 3, 6 and 7. Effector caspases cleave structural proteins, signaling molecules, DNA repair enzymes and proteins which inhibit apoptosis. Activation of effector, or executioner, caspases has historically been viewed as a terminal event in the process of programmed cell death. Emerging evidence now suggests a broader role for activated caspases in cellular maturation, differentiation and other non-lethal events. The importance of activated caspases in normal cell development and signaling has recently been extended to the CNS where these proteases have been shown to contribute to axon guidance, synaptic plasticity and neuroprotection. This review will focus on the adaptive roles activated caspases in maintaining viability, the mechanisms by which caspases are held in check so as not produce apoptotic cell death and the ramifications of these observations in the treatment of neurological disorders.

Topics: Animals; Brain; Brain Ischemia; Calpain; Caspase Inhibitors; Caspases; Central Nervous System; Enzyme Inhibitors; Humans; Nervous System Diseases; Proteasome Endopeptidase Complex

The number of mammalian calpain protease family members has grown to 14 on last count. Overactivation of calpain 1 and calpain 2 (and their small subunit) has long been tied to acute neurological disorders (e.g. stroke and traumatic brain injury) and recently to Alzheimer's disease. Loss-of-function mutations of the calpain 3 gene have now been identified as the cause of limb-girdle muscular dystrophy 2A. Calpain 10 was recently identified as a susceptibility gene for type 2 diabetes, whereas calpain 9 appears to be a gastric cancer suppressor. This review describes our current understanding of the calpain family members and their mechanistic linkages to the aforementioned diseases as well as other emerging pathological conditions.

Topics: Alzheimer Disease; Animals; Calpain; Cataract; Diabetes Mellitus, Type 2; Disease; EF Hand Motifs; Humans; Multigene Family; Muscular Dystrophies; Nervous System Diseases; Stomach Neoplasms

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIβ (CaMKIIβ). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIβ, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.

Topics: Animals; Calpain; Cells, Cultured; Glutamic Acid; Mice; Nervous System Diseases; Neurons; Neuroprotection; Proteolysis; Rats

A previous in vitro study reported that the monoterpene oxide 1,8-cineole (cineole) attenuates neuronal caused by oxygen-glucose deprivation/reoxygenation in culture. However, to date, there is no in vivo evidence showing neuroprotective effects of cineole against stroke. This study aimed to investigate whether cineole attenuates cerebral ischaemic damage in rats.. A rat model of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion was applied. Male rats were treated with oral cineole (100 mg/kg) for 7 consecutive days, then subjected to MCAO surgery. Infarct volume, neurologic deficits, apoptosis and expression levels of all-spectrin breakdown products of 145 kDa (SBDP145), transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylated CREB (p-CREB) were measured in ischaemic brain tissues.. Cineole treatment significantly reduced infarct volume, neurological dysfunction, neuronal apoptosis, SBDP145 formation and TRPC6 degradation and enhanced p-CREB expression in MCAO rats compared with vehicle treatment. These neuroprotective effects were markedly suppressed by pharmacological inhibition of MEK or CaMKIV signalling.. Our study provides in vivo evidence demonstrating that cineole pretreatment attenuates ischaemic stroke-induced brain damage, mainly through blocking calpain-induced TRPC6 degradation and activating CREB via MEK/CREB and CaMKIV/CREB signalling pathways.

Topics: Animals; Apoptosis; Calpain; Cyclic AMP Response Element-Binding Protein; Eucalyptol; Ischemic Stroke; Nervous System Diseases; Neuroprotective Agents; Rats; Signal Transduction; Spectrin; Treatment Outcome; TRPC Cation Channels

Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.

Topics: Animals; Calpain; Cell Death; Corpus Striatum; Cyclin-Dependent Kinase 5; Disease Models, Animal; Estrogens; Female; Glial Fibrillary Acidic Protein; Hypoxia; In Vitro Techniques; Infarction, Middle Cerebral Artery; Male; Mice, Knockout; Nerve Tissue Proteins; Nervous System Diseases; Neurons; Phosphotransferases; Rats; Rats, Sprague-Dawley; Tetrazolium Salts; Time Factors; Tissue Plasminogen Activator

Taurine, an abundant amino acid in the nervous system, is reported to reduce ischemic brain injury in a dose-dependent manner. This study was designed to investigate whether taurine protected brain against experimental stroke through affecting mitochondria-mediated cell death pathway. Rats were subjected to 2-h ischemia by intraluminal filament, and then reperfused for 22 h. It was confirmed again that taurine (50 mg/kg) administered intravenously 1 h after ischemia markedly improved neurological function and decreased infarct volume at 22 h after reperfusion. In vehicle-treated rats, the levels of intracellular ATP and the levels of cytosolic and mitochondrial Bcl-xL in the penumbra and core were markedly reduced, while the levels of cytosolic Bax in the core and mitochondrial Bax in the penumbra and core were enhanced significantly. There was a decrease in cytochrome C in mitochondria and an increase in cytochrome C in the cytosol of the penumbra and core. These changes were reversed by taurine. Furthermore, taurine inhibited the activation of calpain and caspase-3, reduced the degradation of αII-spectrin, and attenuated the necrotic and apoptotic cell death in the penumbra and core. These data demonstrated that preserving the mitochondrial function and blocking the mitochondria-mediated cell death pathway may be one mechanism of taurine's action against brain ischemia.

Topics: Adenosine Triphosphate; Animals; bcl-2-Associated X Protein; bcl-X Protein; Brain Ischemia; Calpain; Caspase 3; Cell Death; Cerebral Infarction; Cytochromes c; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mitochondria; Nervous System Diseases; Rats; Rats, Sprague-Dawley; Stroke; Taurine

Calpain-mediated cleavage of neuronal targets has long been associated with excitotoxicity and synaptic plasticity. In this issue of Neuron, two papers by Xu et al. and Abe and Takeichi explore the respective roles of mGluR1alpha cleavage in excitotoxicity and beta-catenin cleavage in transcriptional control. Together, these papers show the functional importance of fragments of calpain-mediated cleavage.

Topics: Animals; beta Catenin; Calpain; Nervous System Diseases; Neuronal Plasticity; Phosphatidylinositol 3-Kinases; Receptors, Metabotropic Glutamate; Signal Transduction; Transcription, Genetic

Possible biochemical events involved in L-2-chloropropionic acid (L-CPA)-induced delayed cerebellar granule cell necrosis following N-methyl-D-aspartate activation were studied in vivo. We examined whether the calcium-sensitive proteolytic enzymes, the calpains, may be activated by L-CPA or whether the generation of excess quantities of cytotoxic free radicals may play a role in the neurotoxicity produced by oral administration of L-CPA (750 mg/kg, pH 7.0). Evidence for free radical-induced cellular damage was examined using biochemical approaches such as examining brains from L-CPA-treated rats for increased lipid peroxidation, DNA damage, or protein oxidation. Second, the ability of antioxidants to provide neuroprotective activity against L-CPA-induced neurotoxicity was examined in vivo. Western blotting using antibodies against spectrin (alpha-fodrin) demonstrated evidence for calpain (EC 3.4.22.17) activation in the cerebellum, but not in the cerebral cortex of L-CPA-treated rats at 36 and 48 hr after L-CPA dosing. In contrast, there was no evidence for oxidative damage to cerebellar proteins or lipids in L-CPA-treated rat brains compared to controls. We also could not find evidence for DNA damage using the TUNEL method for the detection of single- and/ or double-strand breakage in situ in L-CPA-treated brains. We examined whether a number of reported antioxidants may be effective against L-CPA-induced neurotoxicity. The aminosteroids U74389G and U83836E, the free radical scavengers 3-methyl-1-phenylpyrazolin-5-one and N-tert-butylphenylnitrone, and the iron chelator N-ethoxy-2-ethyl-3-hydroxypyridin-4-one were all ineffective in attenuating L-CPA neurotoxicity. We suggest that L-CPA-induced cerebellar necrosis is the result of calpain activation which results in the degradation of cytoskeletal proteins and other proteins necessary for cellular biochemistry. We could find no evidence of oxidative damage to cerebellar proteins, lipids, or DNA as a result of excess amounts of free radicals, and selective antioxidants were unable to provide neuroprotection against L-CPA neurotoxicity, suggesting that oxidative stress does not play a role in the granule cell necrosis.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Aspartic Acid; Blotting, Western; Calpain; Cerebellum; Free Radicals; Glutamic Acid; Hydrocarbons, Chlorinated; Lipid Peroxidation; Male; Necrosis; Nervous System Diseases; Neurons; Oxidative Stress; Propionates; Rats; Spectrin

Diisopropyl phosphorofluoridate (DFP) produces delayed neurotoxicity (OPIDN) in hens that is characterized by peripheral and central axonal degeneration. DFP administration resulted in mCANP activity inhibition in sciatic nerve and significant decrease in total NF-H, phosphorylated NF-H, vimentin, GFAP, tubulin, and tau. The degradation of cytoskeletal proteins even in the presence of decreased CANP activity may be ascribed to the release of intracellular Ca2+, elevation of other proteinase activity, or modification of cytoskeletal proteins resulting in their increased susceptibility in OPIDN.

Topics: Animals; Antibodies, Monoclonal; Autoradiography; Brain Chemistry; Calpain; Chickens; Cytoskeletal Proteins; Female; Isoflurophate; Nervous System Diseases; Sciatic Nerve; Spinal Cord

The effects of a membrane-permeable inhibitor of calpain, Cbz-Val-Phe-H, were examined in an in vitro model of neurotoxicity. Cerebellar slices from young rats were treated with the glutamate receptor agonist, amino-3-hydroxy-5-methyl-4-isoazole propionic acid (AMPA), and cytotoxicity was quantified using conventional histological techniques. Slices treated with AMPA exhibited damage to 83.0% of cerebellar Purkinje cells. In contrast, only 23.6% of Purkinje cells were damaged in slices treated with Cbz-Val-Phe-H and AMPA. These findings indicate that calcium-activated proteolysis is a critical event in AMPA-induced toxicity, and provide evidence that calpain inhibitors are capable of attenuating this form of excitotoxic damage in the central nervous system.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amino Acid Sequence; Animals; Calpain; Cerebellum; Dipeptides; Female; Ibotenic Acid; Molecular Sequence Data; Nervous System Diseases; Pregnancy; Purkinje Cells; Rats; Rats, Sprague-Dawley