Enviromimetics as a therapeutic lead for Huntington’s disease

Beneficial environmental modulation, such as EE, has been shown to improve cognitive and motor functions in a wide range of neurological disorders, including HD, Alzheimer’s disease, Parkinson’s disease (Nithianantharajah & Hannan, 2006), schizophrenia (Burrows & Hannan, 2016) and autism spectrum disorder (Aronoff Hillyer & Leon, 2016). Although all these disorders have distinct etiologies, enrichment and exercise have shown behavioural positive effects through different molecular mechanisms, as reviewed elsewhere (Nithianantharajah & Hannan, 2006).

While most studies focus on finding new treatments based on pathological molecular/cellular mechanisms, another interesting approach is to enhance the effect of positive environmental modulation by mimicking the molecular mechanisms of experience-dependent plasticity (McOmish & Hannan, 2007). Those drugs would therefore induce the beneficial effects seen after exposure to a stimulating environment, with less individual variability and more control over administration (ibid.).

As EE has been shown to rescue BDNF protein levels in striatum and hippocampus of preclinical models of HD, the development of treatments increasing BDNF signalling, either through enhancement of its expression or stimulation of its receptor, has gained interest. The fact that a deficiency in BDNF signalling is sufficient to cause neuronal loss and dendritic abnormalities in the striatum and cortex highlights its importance in the pathogenesis of HD (Baquet, 2004). Moreover, its role in neuronal survival and neurogenesis makes it an important therapeutic target for neurodegenerative disorders. However, targeting BDNF for the development of therapeutics is challenging due to treatment deliver)' challenges (low brain bioavailability) and the short half-life of the recombinant protein. Furthermore, levels of one of the BDNF receptors, TrkB (tropomyosin receptor kinase B), are reduced in HD patients and mouse models (Brito et al., 2013; Zuccato et al., 2008), implying that a TrkB ligand has to be administered as a therapy before severe TrkB loss to still have a therapeutic effect. Studies have tried different deliver)' methods that could potentially translate to the clinic. The use of an adeno-associated virus (AAV) to express BDNF in the striatum induced longer lifespan and increased neurogenesis in a rat model of HD (Benraiss et al., 2012), but using AAV for gene treatment in patients remains a challenge, mainly since these vectors can induce unwanted immune responses (Colella, Ronzitti & Mingozzi, 2018). Another approach was to use murine (Dey et al., 2010) and human (Pollock et al., 2016) mesenchymal stem cells engineered to produce BDNF. Implantation of these cells into the striatum of transgenic HD mice induced improvements in motor symptoms (Dey et al., 2010), increased neurogenesis and increased lifespan (Pollock et al., 2016). Stem cell-based therapy has shown safety when intracrani- ally injected in patients for other diseases, but has various limitations, especially in the duration of the therapeutic effects. The use of this deliver)' system is awaiting FDA approval to start clinical trials on HD patients (Deng et al., 2016) and could potentially show efficacy in other neurodegenerative disorders such as Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease. Other researchers have focused on non-invasive administration methods for BDNF. For example, da Fonseca and colleagues looked at the efficacy of intra-nasal BDNF treatment on the YAC128 mouse model. Intranasal BDNF treatment could prevent the anhe- donic and depressive-like phenotype in YAC128 mice although it did not induce changes in BDNF levels in the striatum and hippocampus and had no effect on hippocampal neurogenesis. While further studies are needed, it is possible that the effects observed are due to an alteration in BDNF signalling (i.e. activation of TrkB receptors) (da Fonseca et al., 2018).

Indeed, another way to enhance BDNF signalling is to target its TrkB (Simmons, 2017) and p75NTR receptors (ibid.). Small molecules acting as TrkB ligands, that are able to cross the blood brain barrier, have been identified through screening methods. However, these molecules only act as partial agonists, initiating different signalling pathways than those induced by the endogenous neurotrophins. Among these, 7,8-dihydroxyflavone (7,8-DHF) has shown therapeutic efficacy in various models of neurodegenerative diseases related to deficient BDNF signalling (amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease and Rett syndrome) (Liu, Chan & Ye, 2016), including HD. Oral administration of 7,8-DHF ameliorated cerebral volume loss, increased neurogenesis and striatal DARPP-32 levels, and improved motor performance and survival in HD mouse models (N171-82Q and R6/1) (Barriga et al., 2017; Jiang et al., 2013). Another TrkB ligand tested on HD mouse models is the LM22A-4 molecule. This molecule improved motor functions, increased striatal neuron survival and decreased huntingtin aggregates in the R6/2 and BACHD mice (Simmons et al., 2013). Altogether, these results indicate that TrkB ligands are a potential new strategy to treat HD, although these molecules have not reached clinical trials yet.

The p75 neurotrophin receptor is also involved in disease progression, due to an imbalance in its deleterious and survival/trophic signalling. In contrast to the TrkB receptor, p75NrR expression and deleterious signalling are increased in HD mouse models and patients (Brito et al., 2013). A molecule targeting p75NTR and capable of enhancing its trophic signalling, LM11A-31, has shown beneficial effects on the R6/2 and BACHD mice. LM11A-31 reduced huntingtin aggregates, ameliorated cognitive and motor functions and improved survival. More interestingly, this molecule is currently in phase Ila clinical trials for Alzheimer’s disease and has shown safety in phase I, making it a potential candidate molecule for HD (Simmons et al., 2016).

Other drugs have been shown to increase BDNF signalling in HD mice such as antidepressants (sertraline; Peng et al., 2008) and glutamate receptor modulators (ampakines; Simmons et al., 2009). A new study also showed that a 23 amino-acid peptide of the huntingtin protein, P42, prevents aggregate formation and reduces motor symptoms and neurodegeneration in the R6/2 mouse model, through the enhancement of the BDNF-TrkB signalling (Couly et al., 2018). These mole- cules/peptides support the idea of a BDNF-TrkB-based therapy for HD, but do not target BDNF or TrkB and therefore may be at the core of undesirable effects.

Another enviromimetic target is the cannabinoid receptor, especially cannabi- noid receptor 1 (CB1). The CB1 is a G protein-coupled cannabinoid receptor, which is activated by cannabinoid agonist and can regulate aspects of mood, appetite, nociception, inflammation and memory (Aizpurua-Olaizola et al., 2017). As mentioned above, R6/1 mice under standard housing conditions show loss of cannabinoid CB1 receptor in comparison with their respective wild-type litter- mate controls. Being exposed to an enriched environment not only rescues the depletion of CB1 receptor but also improves the behavioural phenotype, suggesting that supplying cannabinoid pharmacologically can be beneficial (Glass et al., 2004). The effect of cannabinoid has been further investigated. A case report using nabilone, a CB1 agonist, has reported a therapeutic effect by mitigating chorea and irritability (Kluger, Triolo, Jones &Jankovic, 2015; Armstrong & Miyasaki, 2012). However, another line of evidence showed no effect of cannabinoid in a form of cannabidiol (Consroe et al., 1991), Sativex (Lopez-Sendon Moreno et al., 2016), or even nabilone (Curtis, Mitchell, Patel, Ives & Rickards, 2009), on HD patients. Altogether, further research is required to elucidate the roles of cannabinoids and cannabinoid receptors, as well as a variety of other neurotransmitter systems, in HD. These approaches could identify molecular targets for enviromimetics, and thus facilitate development of effective treatments for HD, and possibly also related neurodegenerative diseases.

Concluding remarks

Since the discover)' that environmental enrichment delays onset of disease, HD has provided an exemplar for gene—environment interactions in neurodegenerative diseases, as well as other brain disorders. If cognitive stimulation and physical activity can slow down a monogenic disorder such as HD (which until then was considered the epitome of genetic determinism) then the implication is that all such brain diseases are environmentally modifiable. These findings have proven robust across multiple preclinical models, and have been extended to specific investigations of cognitive stimulation and exercise interventions, as well as the role of stress as a disease modifier. While these preclinical studies in mouse models of HD have led to epidemiological and clinical trial studies, they also have implications for the development of enviromimetics, which can mimic or enhance the therapeutic effects of cognitive stimulation and physical activity. These enviromimetics will not only be effective for HD, but are predicted to exhibit therapeutic efficacy for other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.

Almost 150 years after George Huntington first described HD, and over 25 years since the gene mutation was discovered, we still have no disease modifying treatment for this devastating disease. While this thought is intensely sobering, it also provides inspiration to push forward with both preclinical and clinical studies, so as to deliver hope and eventual therapeutic efficacy for the many affected families around the word.

Abbreviations

  • 5-HT1A serotonin 1A receptor
  • 5-HT1B serotonin IB receptor

AAV adeno-associated virus

ALS amyotrophic lateral sclerosis

BACHD bacterial artificial chromosome

BDNF brain-derived neurotrophic factor

CAG cytosine-adenine-guanine

CB1 cannabinoid receptor 1

DARPP-32 dopamine and cAMP regulated neuronal phosphoprotein

EE environmental enrichment

FDA Food and Drug Administration

FID Huntington’s disease

HPA hypothalamic-pituitary-adrenal

HTT huntingtin

IGF-1 insulin-like growth factor 1

MPTP 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine

P75NTR neurotrophin receptor p75

TrkB tropomyosin receptor kinase В

WT wild-type

YAC yeast artificial chromosome

Notes

  • 1 Wild-type refers to animals carrying the most prevalent or ‘normal’ allele, in contrast with mutants carrying the mutated allele,
  • 2 The OX maze apparatus consists of a square box (60 cm x 60 cm x 30 cm) in which are positioned 6 holed blocks,each with a symbol (О,X, =, II). A reward (food pellet made of flour, sugar and sunflower oil) is located in one of the 4 symbols and the number of correct and incorrect nose pokes are recorded.
  • 3 Test in which the participant has to connect dots with numbers and letters in order.
 
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