A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Post, Julia; Kogel, Vanessa; Schaffrath, Anja; Lohmann, Philipp; Shah, N. Jon; Langen, Karl‐Josef; Willbold, Dieter; Willuweit, Antje; Kutzsche, Janine

doi:10.3390/molecules26061590

Cited by 8 publications

(5 citation statements)

References 76 publications

(94 reference statements)

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“…Recently, the CARP RD2RD2 (ptlhthnrrrrrptlhthnrrrrr; +10.4 charge) was investigated as a potential therapeutic candidate for amyotrophic lateral sclerosis (ALS) in a mouse model of mutant superoxide dismutase 1 (SOD1) expression (Post et al, 2021). Administration of RD2RD2 was associated with reductions in motor deficits and neuroinflammation, although the precise molecular mechanisms underlying these effects remain to be elucidated.…”

Section: Potential Roles For Arginine In Other Neurodegenerative Disease-associated Proteopathiesmentioning

confidence: 99%

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Mamsa

Meloni

2021

Front. Mol. Neurosci.

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A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.

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Section: Potential Roles For Arginine In Other Neurodegenerative Disease-associated Proteopathiesmentioning

confidence: 99%

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Mamsa

Meloni

2021

Front. Mol. Neurosci.

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“…During this period, disease progression was analyzed in several behavioral and motoric tests and compared to non-transgenic littermates. For a detailed description of experimental procedures, we refer to our previous studies [ 4 , 5 ].…”

Section: Methodsmentioning

confidence: 99%

“…In a proof-of-concept study in a transgenic AD mouse model, a prominent effect of RD2RD2 on inflammation was observed. Subsequently, it was tested in a mouse model of amyotrophic lateral sclerosis (ALS) [ 4 , 5 ], another neurodegenerative disease known to be strongly influenced by inflammatory processes [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival

et al. 2023

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2–5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients’ benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1*G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1*G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms.

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“…In a study, Post et al [129] examined the therapeutic potential of d-enantiomeric peptide RD2RD2 in the ALS SOD1*G93A transgenic mouse model. Compared to the placebo control, mice treated with RD2RD2 peptide had minimized activated microglia and astrocytes in the brainstem and lumbar spinal cord.…”

Section: Alsmentioning

confidence: 99%

Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications

Giri,

Banerjee,

Ghosal

et al. 2024

IJMS

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Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.

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A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Cited by 8 publications

References 76 publications

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival

Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications

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