Peptide based therapy for neurological disorders

2021 ◽  
Vol 22 ◽  
Author(s):  
Asmita Yadav ◽  
Damini Pandey ◽  
Ghulam Md Ashraf ◽  
Rachana
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
High Throughput Screening ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Eukaryotic Cells ◽  
Haemolytic Activity ◽  
Peptide Bonds ◽  
Intestinal Peptides ◽  
Vasoactive Intestinal Peptides

: Peptides are small molecules composed of amino acids linked together by peptide bonds. The targeted action of these peptides along with their magnificent ability to reach locations in body that are complicated to access, is being considered of tremendous potential in disease modifying therapies. Synthetic as well as natural peptides like Carnosine are currently under research for treatment of neurodegenerative disorders (NDDs). Peptide based vaccines are currently under immense research for diseases like dementia. Toxicity of peptide-based drugs tfigureowards eukaryotic cells due to their increased haemolytic activity is of major concern and this is being tackled by introducing modifications into the peptide structure. Some crucial peptide inhibitors currently in use for neurodegenerative disorders include Aβ (16-20) KLVFF for Alzheimer’s disease, NAPVSIPQ (NAP) for Parkinson’s disease, towards eukaryotic cells Vasoactive Intestinal Peptides (VIP) for Huntington’s disease, Polyglutamine Binding Peptide-1(QBP1) for Dentatorubral-paiidoluysial atrophy (DRPLA). Certain peptides are involved in inhibition of mitochondrial permeability transition (MPT) that plays a prominent part in the materialization of neurodegenerative diseases, one such example of peptides being Ba-V which is obtained from Bothrops atrox snake venom. New therapeutic peptides are being identified using bioinformatics tools like high throughput screening (HTS). These tools are being used to explore the selectivity, stability, extent of immune response and toxic side effects of peptides. Apart from neurodegenerative diseases, the potential of bioactive peptides is also being tested against cancer, diabetes and microbes. This review focuses on the recent advances in peptide therapeutics and novel peptides discovered for treatment of the NDs.

Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice

2007 ◽  
Vol 292 (2) ◽  
pp. C708-C718 ◽  
Author(s):  
Alexander Panov ◽  
Sergey Dikalov ◽  
Natalia Shalbuyeva ◽  
Richelle Hemendinger ◽  
John T. Greenamyre ◽  
...  
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Permeability Transition ◽  
Energy State ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Ros Generation ◽  
Sprague Dawley ◽  
Regenerative Capacity ◽  
Mitochondrial Permeability

In animal models of neurodegenerative diseases pathological changes vary with the type of organ and species of the animals. We studied differences in the mitochondrial permeability transition (mPT) and reactive oxygen species (ROS) generation in the liver (LM) and brain (BM) of Sprague-Dawley rats and C57Bl mice. In the presence of ADP mouse LM and rat LM required three times less Ca2+ to initiate mPT than the corresponding BM. Mouse LM and BM sequestered 70% and 50% more Ca2+ phosphate than the rat LM and BM. MBM generated 50% more ROS with glutamate than the RBM, but not with succinate. With the NAD substrates, generation of ROS do not depend on the energy state of the BM. Organization of the respiratory complexes into the respirasome is a possible mechanism to prevent ROS generation in the BM. With BM oxidizing succinate, 80% of ROS generation was energy dependent. Induction of mPT does not affect ROS generation with NAD substrates and inhibit with succinate as a substrate. The relative insensitivity of the liver to systemic insults is associated with its high regenerative capacity. Neuronal cells with low regenerative capacity and a long life span protect themselves by minimizing ROS generation and by the ability to withstand very large Ca2+ insults. We suggest that additional factors, such as oxidative stress, are required to initiate neurodegeneration. Thus the observed differences in the Ca2+-induced mPT and ROS generation may underlie both the organ-specific and species-specific variability in the animal models of neurodegenerative diseases.

Mitochondria, NO and neurodegeneration

1999 ◽  
Vol 66 ◽  
pp. 43-54 ◽  
Author(s):  
M.Flint Beal
Keyword(s):  
Free Radical ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Point Mutations ◽  
Disease Process ◽  
Permeability Transition ◽  
Free Radical Generation ◽  
Mitochondrial Defects ◽  
Radical Generation

A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.

scholarly journals The Antiaggregative and Antiamyloidogenic Properties of Nanoparticles: A Promising Tool for the Treatment and Diagnostics of Neurodegenerative Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Monika Pichla ◽  
Grzegorz Bartosz ◽  
Izabela Sadowska-Bartosz
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
High Throughput ◽  
Diagnostic Tool ◽  
Neurodegenerative Disorders ◽  
High Throughput Screening ◽  
Promising Tool ◽  
Socioeconomic Burden ◽  
Lateral Sclerosis

Due to the progressive aging of the society, the prevalence and socioeconomic burden of neurodegenerative diseases are predicted to rise. The most common neurodegenerative disorders nowadays, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, can be classified as proteinopathies. They can be either synucleinopathies, amyloidopathies, tauopathies, or TDP-43-related proteinopathies; thus, nanoparticles with a potential ability to inhibit pathological protein aggregation and/or degrade already existing aggregates can be a promising approach in the treatment of neurodegenerative diseases. As it turns out, nanoparticles can be a double-edged sword; they can either promote or inhibit protein aggregation, depending on coating, shape, size, surface charge, and concentration. In this review, we aim to emphasize the need of a breakthrough in the treatment of neurodegenerative disorders and draw attention to nanomaterials, as they can also serve as a diagnostic tool for protein aggregates or can be used in a high-throughput screening for novel antiaggregative compounds.

scholarly journals Interaction of misfolded proteins and mitochondria in neurodegenerative disorders

2017 ◽  
Vol 45 (4) ◽  
pp. 1025-1033 ◽  
Author(s):  
Andrey Y. Abramov ◽  
Alexey V. Berezhnov ◽  
Evgeniya I. Fedotova ◽  
Valery P. Zinchenko ◽  
Ludmila P. Dolgacheva
Keyword(s):  
Neurodegenerative Disorders ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Brain Regions ◽  
Calcium Handling ◽  
Mitochondrial Energy Metabolism ◽  
The People ◽  
The Common ◽  
Β Amyloid

The number of the people affected by neurodegenerative disorders is growing dramatically due to the ageing of population. The major neurodegenerative diseases share some common pathological features including the involvement of mitochondria in the mechanism of pathology and misfolding and the accumulation of abnormally aggregated proteins. Neurotoxicity of aggregated β-amyloid, tau, α-synuclein and huntingtin is linked to the effects of these proteins on mitochondria. All these misfolded aggregates affect mitochondrial energy metabolism by inhibiting diverse mitochondrial complexes and limit ATP availability in neurones. β-Amyloid, tau, α-synuclein and huntingtin are shown to be involved in increased production of reactive oxygen species, which can be generated in mitochondria or can target this organelle. Most of these aggregated proteins are capable of deregulating mitochondrial calcium handling that, in combination with oxidative stress, lead to opening of the mitochondrial permeability transition pore. Despite some of the common features, aggregated β-amyloid, tau, α-synuclein and huntingtin have diverse targets in mitochondria that can partially explain neurotoxic effect of these proteins in different brain regions.

scholarly journals Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

2018 ◽  
Vol 1 (3) ◽  
pp. e00058
Author(s):  
E.F. Shevtsova ◽  
D.V. Vinogradova ◽  
M.E. Neganova ◽  
P.N. Shevtsov ◽  
B.V. Lednev ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Permeability Transition ◽  
Senile Dementia ◽  
Permeability Transition ◽  
Synaptic Activity ◽  
New Drugs ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Important Target ◽  
Mitochondrial Functions

The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimer′s disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimer′s disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest – both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.

scholarly journals Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases

2019 ◽  
Vol 20 (20) ◽  
pp. 4976 ◽  
Author(s):  
Anastasiia Bohush ◽  
Paweł Bieganowski ◽  
Anna Filipek
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Functional Activity ◽  
Protein Misfolding ◽  
Three Dimensional ◽  
Heat Shock Protein 90 ◽  
Eukaryotic Cells

Proper folding is crucial for proteins to achieve functional activity in the cell. However, it often occurs that proteins are improperly folded (misfolded) and form aggregates, which are the main hallmark of many diseases including cancers, neurodegenerative diseases and many others. Proteins that assist other proteins in proper folding into three-dimensional structures are chaperones and co-chaperones. The key role of chaperones/co-chaperones is to prevent protein aggregation, especially under stress. An imbalance between chaperone/co-chaperone levels has been documented in neurons, and suggested to contribute to protein misfolding. An essential protein and a major regulator of protein folding in all eukaryotic cells is the heat shock protein 90 (Hsp90). The function of Hsp90 is tightly regulated by many factors, including co-chaperones. In this review we summarize results regarding the role of Hsp90 and its co-chaperones in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and prionopathies.

scholarly journals Focused design of polypharmacophoric neuroprotective compounds: Conjugates of γ-carbolines with carbazole derivatives and tetrahydrocarbazole

2017 ◽  
Vol 89 (8) ◽  
pp. 1167-1184 ◽  
Author(s):  
Galina F. Makhaeva ◽  
Vladimir B. Sokolov ◽  
Elena F. Shevtsova ◽  
Nadezhda V. Kovaleva ◽  
Sofya V. Lushchekina ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Permeability Transition ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Permeability Transition ◽  
Normal Structure ◽  
Therapeutic Agents ◽  
Tubulin Polymerization ◽  
Biological Targets ◽  
Primary Screening

Abstract Alzheimer’s disease has a complex multifactorial nature; therefore, a promising approach for the development of efficient therapeutic agents is the concept of multitarget drugs, which affect several biological targets involved in the pathogenesis of the disease. We developed a synthetic algorithm for conjugating several pharmacophoric ligands acting on the key stages of pathogenesis of several neurodegenerative diseases and synthesized hybrid structures combining the γ-carboline fragment of Dimebon with carbazole and tetrahydrocarbazole moieties. Using the complex primary screening system the structures have been revealed that combine the high inhibitory activity and selectivity towards butyrylcholinesterase with the radical-scavenging activity and the ability to potentiate tubulin polymerization to microtubules with a normal structure and/or prevent mitochondrial permeability transition. The lead compound was identified for future optimization and development of new multi-target drugs against neurodegenerative diseases combining the cognitive-stimulating and neuroprotective potentials.

770 Preconditioning delays Ca2+-induced mitochondrial permeability transition

2003 ◽  
Vol 2 (1) ◽  
pp. 167 ◽  
Author(s):  
L ARGAUD ◽  
O GATEAUROESCH ◽  
D MUNTEAN ◽  
L GOMEZ ◽  
L CHALABREYSSE ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability
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