Recent years have seen an increase in drug repurposing, an area which itself is fast becoming a hot topic. In this interview, we speak to Elena Minakova, a Fellow in Neonatology at the University of California Los Angeles (UCLA) who is investigating a role for Melanotan-II in reducing social deficits in autism. The drug is, as yet, unapproved by the US FDA, yet has sprung up repeatedly in recent years both in research and as a commercialized product, making this new research particularly interesting.
Could you tell us a little about your background and what first sparked your interest in autism physiology and behavior?
From an early age, I recall being fascinated by the mystery and intricate workings of the brain and mind. I dreamed of becoming a doctor ever since the age of five but always thought I would have a neuroscience-based focus in my pursuits. As an undergraduate at the University of California, San Diego (UCSD; CA, USA), I majored in Physiology and Neuroscience and afterwards, pursued a research-based Master’s in Neuroscience at UCSD. My work at the time was in the field of developmental neurobiology and explored signals involved in neurotransmitter specification during early development of the spinal cord. I was drawn to the neurodevelopmental branch of neuroscience due to the increased plasticity of the nervous system and opportunities to provoke positive changes within aberrant processes with potential for clinical applications.
After completion of the Master’s of Science degree, I went to medical school, completed residency and am currently a Fellow in Neonatology at UCLA. During my fellowship, I continued my enthusiasm for neurodevelopmental neurobiology research and was particularly fascinated by autism research. In recent years, the development of ‘autistic’ rodent models has helped deepen our understanding of how both genetic and environmental factors can lead to alterations within the brain to manifest as autism. Given the availability of autistic rodent models, this was the best match for my goals to assess therapeutic interventions in a neurodevelopmental disorder with the possibility for translational application.
You recently presented your work, ‘Melanotan-II reverses autistic features in the environmental mouse model of autism’, at Neuroscience 2016 – could you give an overview of this?
My research was aimed at testing the effects of Melanotan-II (MT-II) on a validated environmental mouse model of autism. MT-II is a drug with the ability to bind melanocortin receptors on oxytocin neurons, followed by subsequent oxytocin release. In the past several years, oxytocin, a pro-social neuropeptide, has received attention as a possible medication for autism. However, one of the issues with oxytocin administration is its short half-life in the blood stream and poor permeability from the blood to the brain. Of note, MT-II has a cyclical structure, which allows for easier blood–brain permeability followed by endogenous release of oxytocin.
We produced autistic mice through in utero exposure to maternal inflammation and then implanted a subcutaneous pump containing the MT-II. A cannula was placed into the ventricles of the brain and the drug was administered continuously via the subcutaneous pump over a 7-day period. The autistic mice showed significant improvement in their social interactions with several behavioral metrics normalizing to levels found within normal mice. Of interest, the autistic mice receiving the drug were full-fledged adults, suggesting the ability to provoke changes even at less plastic time points in development.
How much do we already know about the role of the melanocortin system in socio-emotional behaviors?
The ability of the melanocortin system to alter socio-emotional behaviors is still a novel area of research. Several recent publications involving animal models showed a number of interesting findings in relation to social bonding and improvement of social deficits. For instance, a study from Meera Modi and Larry Young (both of Emery University, GA, USA) showed that administration of MT-II to prairie voles increased bonding between pair companions. Also, a study published in Science Translational Medicine (2016) from Daniel Geschwind’s laboratory (UCLA) showed that endogenous stimulation of oxytocin release through a melanocortin receptor 4-stimulating agent acutely rescued social deficits in a Cntnap2 genetic mouse model of autism.
In your study, how do you predict that administration of MT-II affected social behaviors (i.e. by what mechanism)?
At this stage, the precise mechanisms of action explaining the improvements of social cognition are not well delineated and could be due to a multitude of pathways. Melanocortin receptor 4 is widely expressed in the brain and includes key areas involved in socio-emotional processing including the amygdala, hippocampus and nucleus accumbens. I hypothesize the improvement in behavior is due to both increased oxytocin release from the paraventricular nucleus and oxytocin-mediated neuromodulatory effects altering emotional and fear processing within the amygdala.
Stimulation of melanocortin receptor 4 has also been shown to increase expression of excitatory glutamatergic receptors on neurons. Some of the cognitive deficits implicated in autism involve a dysregulation of the balance between excitatory and inhibitory neurotransmitters leading to abnormal communication between neuronal networks. One study showed that activation of melanocortin receptors in the hippocampus helped increase memory and plasticity within the region through increased excitatory signal transmission.
Do you think that these findings could lead to the development of new treatments for autism in humans in the future?
I think that if the mechanism of action involving MT-II and socio-emotional improvement is shown, the drug could potentially be used in humans for autism disorder. One of the attractive aspects of studying the melanocortin pathway in rodents is the finding of a highly conserved melanocortin pathway in mammals. However, caution is of course needed when applying findings from ‘autistic’ animal models to actual human treatments.
MT-II is, as yet, unapproved by the US FDA, yet has sprung up repeatedly in recent years both in research and as a commercialized product – what are the other uses for the drug? How could its existing uses and controversies impact on future research and the potential use of the drug to reduce social deficits?
MT-II is an analogue of a- melanocyte stimulating hormone and has the ability to affect multiple complex melanocortin pathways found within the CNS and other peripheral organs such as the skin. As a commercialized product, MT-II has been purchased as a tanning agent due to its ability to stimulate skin pigmentation production. The drug also has the ability to stimulate other pathways in the brain leading to a decrease in appetite.
As of June 2015, Phase II clinical trials were underway for genetic syndromes associated with over-eating, including Prader-Willi Syndrome and a rare form of obesity called POMC-Null Obesity. However, a- melanocyte stimulating hormone has also been shown to increase erections and there are some unofficial reports for potential increases in blood pressure.
Since this drug has multiple systemic targets, further studies will be important in identifying all possible side effects associated with both short- and long-term use of the medication. Although this drug may be promising for autism therapy, further investigations and basic science studies will be necessary to delineate a specific mechanism of action for explaining the socio-emotional improvements seen with MT-II or any other melanocortin receptor 4-activating medication(s).