Short communication
The potent melanocortin receptor agonist melanotan-II promotes peripheral nerve regeneration and has neuroprotective properties in the rat

https://doi.org/10.1016/S0014-2999(02)02945-XGet rights and content

Abstract

The neurotrophic and neuroprotective potential of the α-melanocyte-stimulating hormone (α-MSH) analog cyclo-[Ac-Nle4,Asp5,d-Phe7,Lys10]α-MSH-(4–10) amide (melanotan-II), a potent melanocortin receptor agonist, was investigated. The sciatic nerve crush model was used as a paradigm to investigate the neurotrophic properties of melanotan-II. Melanotan-II significantly enhanced the recovery of sensory function following a crush lesion of the sciatic nerve in the rat at a dose of 20 μg kg−1 per 48 h, s.c., but not at a dose of 2 or 50 μg kg−1. In addition, we observed that melanotan-II also possesses neuroprotective properties, as it partially protected the nerve from a toxic neuropathy induced by cisplatin. Thus, the present data for the first time demonstrate the effectiveness of the potent α-MSH analog melanotan-II in nerve regeneration and neuroprotection.

Introduction

Over the years, numerous studies have shown the importance of melanocortins in the development and maintenance of the nervous system (Strand et al., 1993). Melanocortin peptides are neuropeptides derived from the precursor molecule pro-opiomelanocortin (POMC) by tissue-specific splicing; they include adrenocorticotropic hormone (ACTH) and α-melanocyte-stimulating hormone (α-MSH).

Several of the melanocortins, including α-MSH, have been shown to improve recovery of function after peripheral nerve damage (for a review, see Strand et al., 1993), as well as after experimental spinal cord injury (Lankhorst et al., 1999). Histological examination of injured nerve after α-MSH treatment has revealed a marked effect on the number of neurofilament positive fibers in the regenerating nerve, indicating that α-MSH increases the number of sprouts formed after damage (Joosten et al., 1999). In addition, results of in vitro studies have demonstrated that α-MSH increases the number and the length of neurites formed in cultured dorsal root ganglion neurons (Haynes and Semenenko, 1989). Although these neurotrophic effects of α-MSH and other melanocortins are well established, the mechanisms underlying these effects remain, as yet, largely unknown.

Adan et al. (1996) demonstrated that α-MSH promotes neurite-like outgrowth in neuro 2A cells through a melanocortin receptor. Neuro 2A cells express several types of melanocortin receptors, but the outgrowth-promoting effect of α-MSH could be blocked with a specific melanocortin MC4 receptor antagonist ([d-Arg]ACTH-(4–10)), suggesting that the melanocortin MC4 receptor is involved in this effect of α-MSH. These findings have been confirmed in a subsequent similar study by Davis et al. (1999).

In the present study, we intended to further explore the possible beneficial effects of cyclo-[Ac-Nle4,Asp5,d-Phe7,Lys10]α-MSH-(4–10) amide (melanotan-II) in peripheral nerve regeneration and neuroprotection. Whereas specific melanocortin receptor antagonists are available, specific melanocortin receptor agonists are not. We, therefore, decided to investigate the effects of the most potent melanocortin receptor ligand, i.e., the cyclic α-MSH-related peptide melanotan-II in sciatic nerve crush and cisplatin-induced neuropathy. Previously, this cyclic ligand was shown to have a high affinity for the melanocortin MC1 and MC4 receptors, with a lower affinity for the melanocortin MC3 and MC5 receptors (see Wikberg, 1999), and to activate the brain melanocortin MC4 receptor in vivo (Adan et al., 1999).

In the present study, we show a dose-dependent facilitation of sensorimotor recovery following a sciatic nerve crush and a protection against cisplatin-induced neuropathy by melanotan-II.

Section snippets

Animals and group sizes

All experiments were performed in accordance with the guidelines of the Committee on the Use of Experimental Animals of Utrecht University. In all experiments, male Wistar rats (U:WU:CPB) were used. The rats were allowed to acclimatize for a week after arrival in our animal facilities. They were housed on sawdust bedding in groups of two in type 3 Macrolon cages. Food (commercial rat chow, Hope Farms, Woerden, The Netherlands) and water were available ad libitum. A 12:12-h light/dark regime was

Melanotan-II facilitates sensory recovery from mechanical injury of the sciatic nerve

In Fig. 1, the data are expressed as the mean percentage of recovery over days. All melanotan-II-treated groups were consistently better in the recovery of sensory function as compared to the saline group. However, only the effect of the 20 μg kg−1 melanotan-II dose reached significance (post-operative days 17–26, ANOVA for repeated measurements, P=0.02).

Cisplatin and body weight

The body weight steadily increased in the age-matched controls. The cisplatin-treated groups had significantly lower body weights as compared

Discussion

In the present study, the efficacy of the potent melanocortin receptor agonist melanotan-II in the treatment of peripheral nerve dysfunction in the rat was investigated. Melanotan-II was found to enhance recovery of sensory function following a crush lesion of the sciatic nerve in the rat. Furthermore, melanotan-II protected against neuropathy induced by cisplatin.

Over the last two decades, many attempts have been made to develop a pharmacotherapy that would enhance recovery of function

References (18)

There are more references available in the full text version of this article.

Cited by (21)

  • Nanoparticle encapsulated oxytocin increases resistance to induced seizures and restores social behavior in Scn1a-derived epilepsy

    2021, Neurobiology of Disease
    Citation Excerpt :

    Although OT and vasopressin are closely related neuropeptides, they likely play different roles in epilepsy. The melanocortin 4 receptor agonist, melanotan (MTII) has previously been shown to elicit a wide range of behavioral effects, including increased sexual behavior(Giuliano et al., 2006; Rossler et al., 2006), improved social behavior(Barrett et al., 2014; Minakova et al., 2019; Modi et al., 2015), peripheral nerve regeneration(Ter Laak et al., 2003), and increased insulin sensitivity(Heijboer et al., 2005). The most pronounced melanotan-mediated effects appear to be on social and sexual behaviors which have been shown to be associated with an increase in endogenous OT release(Modi et al., 2015).

  • Melanocortin receptor agonist ACTH 1-39 protects rat forebrain neurons from apoptotic, excitotoxic and inflammation-related damage

    2015, Experimental Neurology
    Citation Excerpt :

    A number of studies have investigated the protective effects of melanocortins in vivo (reviewed in Catania, 2008). As examples, melanocortins are neuroprotective in animal models of ischemia (Spaccapelo et al., 2013), traumatic brain injury (Schaible et al., 2013) and Alzheimer's disease (Giuliani et al., 2014), as well as in peripheral nerve development, protection and repair (Strand et al., 1993; Gispen et al., 1994; Ter Laak et al., 2003). While the mechanisms underlying these effects could arise from peripheral actions such as release of CS and peripheral anti-inflammatory effects, some of the protection could arise from direct protection on neurons within the CNS or PNS.

  • Brain effects of melanocortins

    2009, Pharmacological Research
  • Neuroprotective actions of melanocortins: a therapeutic opportunity

    2008, Trends in Neurosciences
    Citation Excerpt :

    Sciatic nerve recovery following crush lesion was likewise accelerated by α-MSH, ACTH (4–10), ACTH (4–9) and its analog ORG2766 [62,63]. The α-MSH analog cyclo-[Ac-Nle4, Asp5, DPhe7,Lys10]-α-MSH (4–10) amide (melanotan II), a potent MC4R agonist, significantly enhanced the recovery of sensory function following crush lesion of the sciatic nerve in rats [64]. In addition to neurotrophic effects, melanotan II showed neuroprotective properties, as it partly preserved the nerve from a toxic neuropathy induced by cisplatin [64].

  • Effects of Topiramate on the Chronic Constriction Injury Model in the Rat

    2006, Journal of Pain
    Citation Excerpt :

    Neuroprotection may be dose dependent but was not detected even at 40 mg/kg8 and dose-response studies demonstrate ceiling effects.13,22,31 Peripheral neuroprotection by a systemic agent has not been widely demonstrated; melanocortin receptor agonists25,35 and nerve growth factor36 have shown some protective effect in experimental traumatic and cytotoxic neuropathies, respectively. Of interest is the observation that topiramate in this experiment seemed to encourage weight gain in CCI rats relative to CCI rats that received saline.

View all citing articles on Scopus
View full text