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Drug repositioning: diacerein as a new therapeutic approach in a mice model of sciatic nerve injury

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Abstract

Background

Peripheral nerve injuries negatively impact the quality of life of patients, with no effective treatment available that accelerates sensorimotor recovery and promotes functional improvement and pain relief. The aim of this study was to evaluate the effects of diacerein (DIA) in an experimental mice model of sciatic nerve crush.

Method

In this study, male Swiss mice were used, randomly separated into six groups as follows: FO (false-operated + vehicle); FO + DIA (false-operated + diacerein 30 mg/kg); SNI (sciatic nerve injury + vehicle); SNI + DIA in doses of 3, 10 and 30 mg/kg (sciatic nerve injury + treatment with diacerein in doses of 3–30 mg/kg). DIA or vehicle was administered 24 h after the surgical procedure, intragastrically, twice a day. The lesion of the right sciatic nerve was generated by crush.

Results

We found that the treatment of animals with DIA accelerated sensorimotor recovery of the animal. In addition, animals in the sciatic nerve injury + vehicle (SNI) group showed hopelessness, anhedonia, and lack of well-being, which were significantly inhibited by DIA treatment. The SNI group showed a reduction in the diameters of nerve fibers, axons, and myelin sheaths, while DIA treatment recovered all these parameters. In addition, the treatment of animals with DIA prevented an increase the levels of interleukin (IL)-1β and a reduction in the levels of the brain-derived growth factor (BDNF).

Conclusions

Treatment with DIA reduces hypersensitivity and depression like behaviors in animals. Furthermore, DIA promotes functional recovery and regulates IL-1β and BDNF concentrations.

Graphical abstract

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the curve

BDNF:

Brain-derived neurotrophic fator

CEUA:

Ethics committee for using animals in research

DAX:

Diameter of the axon

DBM:

Diameter of the myelin sheath

DFN:

Diameter of the nerve fiber

DIA:

Diacerein

ELISA:

Enzyme-linked immunosorbent assay

EPL:

Measurements length of the paw of the experimental side

ETS:

Measurements total spread of the fingers of the experimental side

NF:

Nerve fibers

FO:

False-operated

HE:

Hematoxylin and eosin

HL:

Horizontal ladder

IL:

Interleukin

IL–1β:

Interleuckin 1 beta

LAMEB:

Multiuser laboratory of biology studies

MMPs:

Metalloprotease

MMP-2:

Metalloprotease 2

MMP-9:

Metalloprotease 9

N/mm2 :

Density of nerve fibers

NPL:

Measurements length of the paw of the normal side

NTS:

Measurements total spread of the fingers of the normal side

OA:

Osteoarthritis

PBS:

Phosphate buffer

PE:

Perineurium

PL:

Print length

PNIs:

Peripheral nerve injuries

SCs:

Schwann cells

SEM:

Standard error of the mean

SFI:

Sciatic functional index

SNI:

Sciatic nerve injury

TNF-α:

Tumor necrosis factor alpha

TS:

Total spread

UFSC:

Federal University of Santa Catarina

WD:

Wallerian degeneration

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Funding

This article is dedicated to the memory of Prof. Dr. Adair Roberto Soares dos Santos. We are immensely grateful to Prof. Adair, a great friend and instructor, who contributed intensely to our work (Concept, idea, research design and providing facilities) and recently passed away, being deeply missed. We also thank Neuroscience Post-Graduate Program at the Federal University of Santa Catarina (UFSC), Multiuser Laboratory of Biology Studies (LAMEB/UFSC) and the Centro de Inovação e Ensaios Pré-Clínicos (CIEnP) for the support in some stages of the experiments. This study was financed in part by the Programa INCT-INOVAMED (465430/2014–7) grant; and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. The graphical abstract was created using the Mind the Graph@, regularly contemplated by the author MDS.

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Authors and Affiliations

  1. Laboratory of Neurobiology of Pain and Inflammation (LANDI), Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, University Campus, Trindade, Florianópolis, SC, 88040-900, Brazil

    Jhenifer Karvat, Tassiane Emanuelle Servare Andrade, Scheila Iria Kraus, Larissa May Beppler, Gustavo dos Santos Catarina de Jesus, Jeane Bachi Ferreira & Morgana Duarte da Silva

  2. Program of Post-Graduation in Neuroscience, Federal University of Santa Catarina, University Campus, Trindade, Florianópolis, SC, 88040-900, Brazil

    Jhenifer Karvat, Tassiane Emanuelle Servare Andrade, Scheila Iria Kraus & Morgana Duarte da Silva

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  1. Jhenifer Karvat
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Contributions

Concept/idea/research design: JK, ARSS, MDS. Writing: JK, MDS. Data collection and Data analysis: JK, TESA, SIK, LMB, GSCJ, JBF, MDS. Providing facilities/equipment and institutional liaisons: ARSS, MDS.

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Correspondence to Morgana Duarte da Silva.

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Karvat, J., Andrade, T.E.S., Kraus, S.I. et al. Drug repositioning: diacerein as a new therapeutic approach in a mice model of sciatic nerve injury. Pharmacol. Rep 75, 358–375 (2023). https://doi.org/10.1007/s43440-023-00461-9

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