Antinociceptive effect of triterpene acetyl aleuritolic acid isolated from Croton zehntneri in adult zebrafish (Danio rerio)
Graphical abstract
Introduction
Pain is a physiological response generated after mechanical tissue damage and inflammation, which can be stimulated by generalized factors being the primary indicator of tissue damage [1]. In order for the painful stimulus to process, it is necessary for nociceptors to be activated by mechanical, physical, including thermal (temperature 34 to 43 °C) or chemical stimuli, through mediation by nociceptive agents such as: formalin, capsaicin, glutamate, acid saline, and solution hypertonic saline [2,3].
Tactile and painful sensations in the cornea are captured by innervations that arise from the first branch of the trigeminal nerve [4]. The debilitating discomfort of chronic corneal neuropathic pain has an immensely negative impact on patients’ quality of life, causing impaired functioning and inability to perform activities of daily living [5], which promotes the investigation of drugs that inhibit or sensitize endings corneal nerves in the transduction of nociceptive potential [6].
The antinociceptive effect of triterpenes in animal models has been reported [[7], [8], [9], [10], [11], [12]]. AAA is a triterpene of molecular formula C32H50O4 that was isolated from the stem bark of Croton zehntneri, a plant native to Northeast Brazil known as “canelinha de cunhã” [13]. AAA has been identified to have moderate cytotoxic effect [14], anti-inflammatory and analgesic effect in rodents [15].
Zebrafish (D. rerio) has the cellular components necessary to respond to various harmful stimuli [16], as it expresses genes involved in pain neuromodulation such as NMDA, TRPV1, TRPV2, TRPM3, TRPM8, TRPA1, and ASICs [[17], [18], [19], [20]]. Research has used zebrafish to mimic nociceptive behavior and thereby identify new biologically active compounds [2,7,21,22]. In this perspective and based on the reported data, the antinociceptive effect of AAA isolated from the bark of the stem of C. zehntneri and possible mechanisms of action in adult zebrafish (Danio rerio) were investigated.
Section snippets
Triterpene acetyl aleuritolic acid
The triterpene acetyl aleuritolic acid (Fig. 1) was extracted from the stem of C. zehtneri. The plant material was collected in March 2006, in Tianguá, Ceará, Brazil, identified and cataloged under no. 42,389 at Herbário Prisco Bezerra. The characterizations and vibrational properties of the triterpene were carried out by Melo et al. [13].
Drugs and reagents
The drugs and reagents used in the experiments were: formaldehyde, acetic acid (Dinâmica, Brazil), sodium chloride (NaCl; Synth), saline solution (0.9%;
96 h open field test and acute toxicity
No sedation and/or locomotor dysfunction was observed in animals treated with AAA or vehicle (0.9% saline; 20 μL; i.p.). The mobility of animals treated with AAA varied between 86.6 and 93%, with no difference between the Naive group and vehicle (p > 0.05). Animal mortality was also not recorded after 96 h (LC50 > 1.0 mg/mL).
Antinociceptive activity
The highest concentration of AAA [(1.0 mg/mL; 20 μL; i.p.) ∗p < 0.05 vs. control] inhibited neurogenic formalin-induced nociception and acid-saline-induced nociception, as
Discussion
Although the antinociceptive potential of AAA isolated from C. cajucara has been reported [15], it is believed that this is the first study to ascertain the analgesic capacity of AAA isolated from C. zehntneri against various nociceptive stimuli in ZFa. In this study, we performed nociceptive models induced by chemical products, and identified the antinociceptive potential of the triterpene AAA through the modulation of receptors in adult zebrafish. There was no toxicity or any change in the
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
We would also like to thank FUNCAP, CAPES, and CNPq for the support and scholarships.
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