Early preclinical screening using zebrafish (Danio rerio) reveals the safety of the candidate anti-inflammatory therapeutic agent TnP

Batista-Filho, João; Falcão, Maria Alice Pimentel; Maleski, Adolfo Luís Almeida; Soares, Amanda Beatriz Silva; Balan-Lima, Leticia; Disner, Geonildo Rodrigo; Lima, Carla; Lopes-Ferreira, Mônica

doi:10.1016/j.toxrep.2020.12.004

Cited by 11 publications

(10 citation statements)

References 58 publications

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“…Tn P demonstrated high stability, high safety, low toxicity ( 5 ) and immunogenicity ( 3 ) added to the ability to cross the blood-brain barrier. These properties lead us to predict a potential ability of interaction with lipid membranes allowing cellular membrane crossing and access to intracellular targets ( 15 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

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TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model

et al. 2022

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TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

“…The low frequency of Tn P-induced abnormalities in embryos was associated with the high safety of the molecule and the ability of the developing embryo to process and eliminate it. Tn P crossed the blood-brain barrier without disturbing the development of the normal architecture of the forebrain, midbrain, and hindbrain ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model

et al. 2022

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“…In view of increasing the TnP dossier, using a patented peptide with immunomodulatory action in a murine model of multiple sclerosis [24], we recently demonstrated that TnP possesses a wide therapeutic index without toxic effects on zebrafish. TnP was safe in preclinical toxicological studies, crossing the blood-brain barrier without disturbing the normal architecture of the brain [15], which is fundamental once it is a candidate for the treatment of neuroinflammation, including neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…The teleost zebrafish (Danio rerio) is a versatile model organism for investigating cellular and molecular mechanisms adjacent to several pathological processes and for monitoring environmental contaminants [9][10][11]. Moreover, zebrafish have been used to evaluate candidate therapeutic agents through preclinical toxicological studies required by the pharmaceutical industry in the initial stage of drug discovery [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

In Silico Target Prediction of Overexpressed microRNAs from LPS-Challenged Zebrafish (Danio rerio) Treated with the Novel Anti-Inflammatory Peptide TnP

Disner

Falcão

Lima

et al. 2021

IJMS

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miRNAs regulate gene expression post-transcriptionally in various processes, e.g., immunity, development, and diseases. Since their experimental analysis is complex, in silico target prediction is important for directing investigations. TnP is a candidate peptide for anti-inflammatory therapy, first discovered in the venom of Thalassophryne nattereri, which led to miRNAs overexpression in LPS-inflamed zebrafish post-treatment. This work aimed to predict miR-21, miR-122, miR-731, and miR-26 targets using overlapped results of DIANA microT-CDS and TargetScanFish software. This study described 513 miRNAs targets using highly specific thresholds. Using Gene Ontology over-representation analysis, we identified their main roles in regulating gene expression, neurogenesis, DNA-binding, transcription regulation, immune system process, and inflammatory response. miRNAs act in post-transcriptional regulation, but we revealed that their targets are strongly related to expression regulation at the transcriptional level, e.g., transcription factors proteins. A few predicted genes participated concomitantly in many biological processes and molecular functions, such as foxo3a, rbpjb, rxrbb, tyrobp, hes6, zic5, smad1, e2f7, and npas4a. Others were particularly involved in innate immunity regulation: il17a/f2, pik3r3b, and nlrc6. Together, these findings not only provide new insights into the miRNAs mode of action but also raise hope for TnP therapy and may direct future experimental investigations.

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“…In addition to the proven therapeutic effects of Tn P in a preclinical mouse model, analyses of its possible mechanisms of action [ 15 , 16 ], therapeutic index, safety and toxicology [ 17 ] were carried out in the zebrafish model organism.…”

Section: Introductionmentioning

confidence: 99%

The Anti-Inflammatory Peptide TnP Is a Candidate Molecule for Asthma Treatment

Lima

Falcão

Pinto

et al. 2023

Cells

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Asthma is the most common chronic lung disease, with increasing morbidity and mortality worldwide. Accumulation of peribronchial leukocytes is the hallmark of asthma, in particular, eosinophils, which have been reported as the primary cell associated with the induction of airway hyperresponsiveness. Continued exacerbation and accumulation of other leukocytes, such as neutrophils, Th1, and Th17 cells correlate with many of the long-term effects of asthma, such as airway remodeling. We have patented the TnP family of synthetic cyclic peptides, which is in the preclinical phase of developmental studies for chronic inflammatory diseases. The aim of this work was to investigate whether TnP could show anti-inflammatory activity in a murine model of asthma that includes a mixed phenotype of eosinophilic and neutrophilic inflammation. For this, Balb/c mice, sensitized with OVA and exposed to 1% challenge with OVA aerosol, were submitted to prophylactic treatment, receiving TnP at 0.3 mg/kg orally, 1 h before each challenge. We found that sensitized mice challenged with OVA and treated with TnP showed no airway hyperreactivity or lung remodeling. TnP acts systemically in secondary lymphoid organs and locally in the lung, inhibiting the production of Th2/Th17 cytokines. Furthermore, TnP prevented the infiltration of eosinophils and neutrophils in the BAL and lung tissue, inhibited the production of IgE/IgG1, prevented hyperplasia of mucus-producing cells, and decreased the thickening and deposition of sub-epithelial collagen. Our results showed TnP as a candidate molecule for the treatment of airway remodeling associated with inflammatory diseases, such as asthma.

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Early preclinical screening using zebrafish (Danio rerio) reveals the safety of the candidate anti-inflammatory therapeutic agent TnP

Abstract: Graphical abstract

Cited by 11 publications

References 58 publications

TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model

TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model

In Silico Target Prediction of Overexpressed microRNAs from LPS-Challenged Zebrafish (Danio rerio) Treated with the Novel Anti-Inflammatory Peptide TnP

The Anti-Inflammatory Peptide TnP Is a Candidate Molecule for Asthma Treatment

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