The Calpain Hypothesis of Neurodegeneration: Evidence for a Common Cytotoxic Pathway

1997 ◽  
Vol 3 (5) ◽  
pp. 314-327 ◽  
Author(s):  
Raymond T. Bartus
Keyword(s):  
Neuronal Damage ◽  
Cytosolic Calcium ◽  
Brain Regions ◽  
Current Evidence ◽  
General Function ◽  
Loss Of Function ◽  
Pathogenic Role ◽  
Wide Range ◽  
Cord Injury ◽  
Alzheimer’S Pathology

Calpain's general function and pathogenic role in the CNS are reviewed. Collectively, the literature indicates that calpain proteolysis plays a common and important role in a variety of acute neurodegenerative conditions, including focal ischemia (stroke), global ischemia, traumatic brain injury, and spinal cord injury. This evidence indicates that 1) calpain is activated in an abnormally sustained fashion during cellular events commonly associated with neurodegeneration (e.g., excessive interstitial glutamate and cytosolic calcium); 2) many of calpain's preferred substrates are degraded as important components in these neurodegenerative conditions; 3) calpain activation occurs early in the pathogenic cascade of each, prior to onset of substantial cell death; and 4) calpain inhibitors can effectively reduce the severity of neuronal damage and loss of function normally associated with these acute neurodegenerative perturbations. Calpain proteolysis is also implicated in chronic neurodegenerative diseases, with the strength of current evidence varying among specific diseases. The evidence accumulated for a plausible role in Alzheimer's disease (AD) is currently the strongest. For example, empirical links have been established between abnormal calpain proteolysis and 1) the cellular formation of classic Alzheimer's pathology, such as β-amyloid plaques, neurofibrillary tangles, and Alz-50 immunoreactivity; 2) the brain regions with greatest concentrations of AD-related pathology; and 3) the degeneration of key brain pathways vulnerable in the early stages of the disease. Similar, though less extensive, evidence exists for a potential role of abnormal calpain proteolysis in Parkinson's disease. Finally, for several other chronic neurodegenerative conditions (e.g., Huntington's disease and amyotrophic lateral sclerosis), early evidence is emerging that calpain may also play some pathogenic role. Thus, these data support the possibility that uncontrolled calpain proteolysis may contribute to and/or accelerate the loss of neurons associated with a wide range of neurodegenerative conditions and may, therefore, represent an important, final common cytotoxic pathway for many diverse forms of neurodegeneration. NEUROSCIENTIST 3:314–327, 1997

scholarly journals Efficacy of Virtual Reality Rehabilitation after Spinal Cord Injury: A Systematic Review

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Amanda Vitória Lacerda de Araújo ◽  
Jaqueline Freitas de Oliveira Neiva ◽  
Carlos Bandeira de Mello Monteiro ◽  
Fernando Henrique Magalhães
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Virtual Reality ◽  
Motor Function ◽  
Current Evidence ◽  
Pain Level ◽  
Positive Effects ◽  
Wide Range ◽  
Cord Injury ◽  
Aerobic Function

Background. Spinal cord injury (SCI) is often associated with long-term impairments related to functional limitations in the sensorimotor system. The use of virtual reality (VR) technology may lead to increased motivation and engagement, besides allowing a wide range of possible tasks/exercises to be implemented in rehabilitation programs. The present review aims to investigate the possible benefits and efficacy of VR-based rehabilitation in individuals with SCI. Methods. An electronically systematic search was performed in multiple databases (PubMed, BVS, Web of Science, Cochrane Central, and Scielo) up to May 2019. MESH terms and keywords were combined in a search strategy. Two reviewers independently selected the studies in accordance with eligibility criteria. The PEDro scale was used to score the methodological quality and risk of bias of the selected studies. Results. Twenty-five studies (including 482 participants, 47.6 ± 9.5 years, 73% male) were selected and discussed. Overall, the studies used VR devices in different rehabilitation protocols to improve motor function, driving skills, balance, aerobic function, and pain level, as well as psychological and motivational aspects. A large amount of heterogeneity was observed as to the study design, VR protocols, and outcome measures used. Only seven studies (28%) had an excellent/good quality of evidence. However, substantial evidence for significant positive effects associated with VR therapy was found in most of the studies (88%), with no adverse events (88%) being reported. Conclusion. Although the current evidence is limited, the findings suggest that VR-based rehabilitation in subjects with SCI may lead to positive effects on aerobic function, balance, pain level, and motor function recovery besides improving psychological/motivational aspects. Further high-quality studies are needed to provide a guideline to clinical practice and to draw robust conclusions about the potential benefits of VR therapy for SCI patients. Protocol details are registered on PROSPERO (registration number: CRD42016052629).

Neuroprotection for Spinal Cord Injury

2017 ◽  
Author(s):  
Christopher S. Ahuja ◽  
Michael Fehlings
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Spinal Cord Injuries ◽  
Current Evidence ◽  
Mechanical Trauma ◽  
Secondary Injury ◽  
Loss Of Function ◽  
Cord Injury ◽  
Death And Loss

Traumatic spinal cord injuries (SCI) often have a devastating impact on quality of life for patients and their families. Neuroprotection for spinal cord injury is aimed at improving functional outcomes by limiting secondary injury processes that occur within the first minutes, hours, and days following the primary injury. The primary mechanical trauma initiates a secondary injury cascade where ischemia, inflammatory cell infiltration, and cytotoxic changes in the microenvironment cause further cell death and loss of function. Time-sensitive neuroprotective measures targeting these secondary insults have emerged as key therapeutic strategies. This chapter summarizes current evidence-based neuroprotective treatments, such as blood pressure augmentation, early surgical decompression, and intravenous methylprednisolone, as well as important emerging interventions, including therapeutic hypothermia, sodium channel blockade using riluzole, and the anti-inflammatory actions of minocycline. The chapter concludes by summarizing the current guidelines that all practitioners should be well-versed in prior to providing care for patients with SCI.

scholarly journals Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

2019 ◽  
Vol 19 (1) ◽  
pp. 131-153 ◽  
Author(s):  
H. Mitoma ◽  
A. Buffo ◽  
F. Gelfo ◽  
X. Guell ◽  
E. Fucà ◽  
...  
Keyword(s):  
Environmental Enrichment ◽  
Pathological Process ◽  
Current Evidence ◽  
Loss Of Function ◽  
Therapeutic Implications ◽  
Ocular Movements ◽  
Immune Mediated ◽  
Wide Range ◽  
Cerebellar Diseases ◽  
Cerebellar Ataxias

AbstractCerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

scholarly journals Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

Diagnostics ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2205
Author(s):  
Andrea Ricci ◽  
Elena Di Pierro ◽  
Matteo Marcacci ◽  
Paolo Ventura
Keyword(s):  
Pyridoxal Phosphate ◽  
Aminolevulinic Acid ◽  
Neuronal Damage ◽  
Current Evidence ◽  
Metabolic Demand ◽  
Clinical Presentations ◽  
Wide Range ◽  
Different Types ◽  
Life Threatening ◽  
Functional Deficiency

Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

scholarly journals SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Wide Range ◽  
Inflammatory State ◽  
Acute Polyneuropathy ◽  
The Central Nervous System ◽  
The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

scholarly journals EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats

2020 ◽  
Vol 11 (1) ◽  
pp. 173-181 ◽  
Author(s):  
Jianjun Wang ◽  
Ying Chen ◽  
Long Chen ◽  
Yanzhi Duan ◽  
Xuejun Kuang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Functional Recovery ◽  
Antioxidant Properties ◽  
Underlying Mechanism ◽  
Maximal Effect ◽  
Loss Of Function ◽  
Protein Kinase D1 ◽  
Erk Phosphorylation ◽  
Cord Injury ◽  
Novel Strategy

AbstractBackgroundSpinal cord injury (SCI) causes devastating loss of function and neuronal death without effective treatment. (−)-Epigallocatechin-3-gallate (EGCG) has antioxidant properties and plays an essential role in the nervous system. However, the underlying mechanism by which EGCG promotes neuronal survival and functional recovery in complete spinal cord transection (ST) remains unclear.MethodsIn the present study, we established primary cerebellar granule neurons (CGNs) and a T10 ST rat model to investigate the antioxidant effects of EGCG via its modulation of protein kinase D1 (PKD1) phosphorylation and inhibition of ferroptosis.ResultsWe revealed that EGCG significantly increased the cell survival rate of CGNs and PKD1 phosphorylation levels in comparison to the vehicle control, with a maximal effect observed at 50 µM. EGCG upregulated PKD1 phosphorylation levels and inhibited ferroptosis to reduce the cell death of CGNs under oxidative stress and to promote functional recovery and ERK phosphorylation in rats following complete ST.ConclusionTogether, these results lay the foundation for EGCG as a novel strategy for the treatment of SCI related to PKD1 phosphorylation and ferroptosis.

scholarly journals The Use of Anterior-Segment Optical-Coherence Tomography for the Assessment of the Iridocorneal Angle and Its Alterations: Update and Current Evidence

2021 ◽  
Vol 10 (2) ◽  
pp. 231
Author(s):  
Giacinto Triolo ◽  
Piero Barboni ◽  
Giacomo Savini ◽  
Francesco De Gaetano ◽  
Gaspare Monaco ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Intraocular Pressure ◽  
Clinical Relevance ◽  
Anterior Segment ◽  
Angle Closure ◽  
Current Evidence ◽  
Optical Coherence ◽  
Iridocorneal Angle ◽  
Wide Range

The introduction of anterior-segment optical-coherence tomography (AS-OCT) has led to improved assessments of the anatomy of the iridocorneal-angle and diagnoses of several mechanisms of angle closure which often result in raised intraocular pressure (IOP). Continuous advancements in AS-OCT technology and software, along with an extensive research in the field, have resulted in a wide range of possible parameters that may be used to diagnose and follow up on patients with this spectrum of diseases. However, the clinical relevance of such variables needs to be explored thoroughly. The aim of the present review is to summarize the current evidence supporting the use of AS-OCT for the diagnosis and follow-up of several iridocorneal-angle and anterior-chamber alterations, focusing on the advantages and downsides of this technology.

scholarly journals The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy

2021 ◽  
Vol 22 (9) ◽  
pp. 4822
Author(s):  
Viktória Kovács ◽  
Gábor Remzső ◽  
Tímea Körmöczi ◽  
Róbert Berkecz ◽  
Valéria Tóth-Szűki ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Kynurenic Acid ◽  
Neuronal Damage ◽  
Brain Regions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Hippocampal Field ◽  
Power Spectral ◽  
Density Values ◽  
Ischemic Encephalopathy

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.

scholarly journals Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence

2021 ◽  
Vol 22 (6) ◽  
pp. 3059
Author(s):  
Corrado Pelaia ◽  
Cecilia Calabrese ◽  
Eugenio Garofalo ◽  
Andrea Bruni ◽  
Alessandro Vatrella ◽  
...  
Keyword(s):  
Review Article ◽  
Lung Damage ◽  
Current Evidence ◽  
Therapeutic Effects ◽  
Cytokine Storm ◽  
Future Perspectives ◽  
Pathogenic Role ◽  
Refractory Rheumatoid Arthritis ◽  
Life Threatening

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab’s therapeutic effects in patients with life-threatening SARS-CoV-2 infection.

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