Building Bridges In Neuropharmacology: New therapeutic approaches for psychiatric and neurodegenerative disorders

This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc In this issue entitled Building Bridges In Neuropharmacology: New therapeutic approaches for psychiatric and neurodegenerative disorders, we will review recent developments from UK- and Brazil-based scientists among others in the treatment of mental health, neurodegenerative and other CNS disorders. This follows the Pharmacology 2019 symposium entitled "Building Bridges In Neuropharmacology: A Joint BPS and Brazilian Society of Pharmacology and Experimental Therapeutics Symposium" where successful collaborations between UK- and Brazil-based scientists in the areas of neuropharmacology including addiction, Parkinson's and Alzheimer's were highlighted. Neuropharmacology encompasses all phases of research—from in vitro studies to clinical trials—and crosses into a multitude of other fields such as behavioural neuroscience and psychiatry, cell biology and biochemistry, organic chemistry, and computational neuroscience, and many, many more. But perhaps equally significantly, the dictionary definition of neuropharmacology also fails to convey the momentum and excitement in the field, as neurological and psychiatric diseases occupy a growing share of the research budgets worldwide, and the search for new treatments for these conditions takes centre stage. This need for new neuropharmaceuticals is perhaps most tangible in the field of neurodegeneration, where the most common neurodegenerative diseases remain incurable. With human life expectancies increasing throughout the world, the burden placed on healthcare systems by these predominantly age-related conditions is certain to increase considerably. It is therefore especially encouraging to know that new pharmacological treatments for neurodegeneration are in the pipeline. For Parkinson's disease, the second most common neurodegenerative disease worldwide, a big research focus over recent years has been on leucine-rich repeat kinase 2 (LRRK2). LRRK2 is a combined kinase and GTPase enzyme that displays increased activity in certain familial forms of Parkinson's disease. Can targeting LRRK2 be a viable strategy to arrest the progression of this condition? Clinical trials into the use of pharmacological LRRK2 kinase inhibitors and antisense oligonucleotides to LRRK2 are currently underway in patients, but importantly, should these molecules fail, numerous alternatives are waiting in the wings (Azeggagh & Berwick, 2022). Other pharmacological targets for neurodegeneration are less disease-specific. One set of drug targets attracting particular interest are sirtuins, a family of NAD+-dependent histone deacetylases (Leite et al., 2022). These enzymes have roles in controlling key events in the cell nucleus, such as gene transcription and DNA repair, in modulating microtubule dynamics in the cytosol and in regulating cellular metabolism at mitochondria. Agents that modulate the activity of sirtuins, most notably the antioxidant resveratrol, are believed to be therapeutically beneficial in a remarkable range of neurodegenerative and psychiatric disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism spectrum disorder (ASD), schizophrenia and bipolar disorder (Leite et al., 2022). Another plant-derived molecule with potential for treating neurodegeneration is ouabain, which is best described as a molecule that acts on the heart but is nonetheless known to be active in the brain. A growing body of data provides convincing evidence that via binding to the enzyme, Na,K-ATPases, and the regulation of intracellular signalling pathways, ouabain is able to induce potent neuroprotective effects (Kinoshita et al., 2022). The modulation of Na,K-ATPase activity plays a key role in excitability, plasticity and cell survival, which could be used to enhance levels of dendritic branching in hippocampal neurons, in association with an improvement in spatial reference memory (Kinoshita et al., 2022). Disorders of the central nervous system (CNS) are of course not limited to neurodegenerative conditions that predominantly occur in old age. At the other end of the spectrum are mental health disorders, which are no less amenable for therapeutic targeting. Despite the increasing socioeconomic cost of these disorders, which even surpasses that of chronic somatic diseases, the development of novel pharmacotherapeutics for the management of mental illnesses has been slow over the last 30 years. However, some promising agents are emerging that may aid the management of these disorders, for example, the neuropeptide oxytocin (Martins et al., 2022) and agents that interact with the vasopressin system (Rae et al., 2022). As pleiotropic neuromodulators of the stress system, the oxytocin and vasopressin systems are considered promising targets or plasma biomarkers of autism spectrum disorder, schizophrenia and substance use disorder. Stressful events and psychosocial challenges are strongly correlated with the progress of these diseases. A potential explanation for considering oxytocin and vasopressin as new pharmacotherapeutics is their role as regulators of anxiety and social–emotional adjustments mainly at the levels of the paraventricular nucleus and amygdala, in particular, via GABA modulation (Rae et al., 2022). Nonetheless, a meta-analysis of repeated intranasal oxytocin clinical trials has failed to demonstrate a profound beneficial effect especially for the treatment of symptoms of autism spectrum disorder and schizophrenia (Martins et al., 2022). However, analysis of the heterogeneity of responses in such studies can reveal subgroups of patients where pharmacotherapy may be effective, such as in the case of treating negative symptoms of schizophrenia with oxytocin. Substance use disorders are conditions where effective pharmacotherapy is limited, risky or not available, and hence another area where effective pharmacotherapeutics are needed. There is evidence that intranasal oxytocin administration may be of benefit due to its anti-craving properties (Houghton et al., 2021 – published in the 178:21 issue of BJP). Studies investigating the role of factors such as treatment regimens and sample characteristics, including the role of the amygdala, which has been proposed as a distinct mechanism mediating oxytocin's anti-craving properties, are warranted. Despite the demand for the treatment of cocaine use disorder, the regulatory agencies for drug safety have not approved any pharmacological treatment for cocaine addiction (Sanchez et al., 2022). Most medications used were developed for other medical conditions. Indeed, drug discovery is complex, time-consuming and very costly. Among the pharmacological agents tested for cocaine use disorder, GABAergic agents have yielded promising findings in clinical and preclinical studies. In particular, GABAA receptor agonists have been shown to counteract cocaine-induced neurochemical and behavioural effects, such as the amplification of phasic dopamine signals in the nucleus accumbens evoked by electrical stimulation on the ventral tegmental area, and appetitive 50-kHz vocalization elicited by cocaine. Understanding the biochemistry underlining opioid and psychostimulant use disorders is critical not only to develop effective pharmacotherapy but also to unravel the all-important biomarkers that allow diagnosis and treatments of diseases and progression to be monitored (Caspani et al., 2022). As such, metabolomic approaches, that is, the analysis of the metabolome, offer a unique biochemical fingerprint that will help uncover the biomolecular perturbations that take place as people transition from recreational use of opioids and psychostimulants to chronic use/abuse and how that varies across individuals. Metabolomics has the potential to facilitate the implementation of precision medicine interventions to achieve faster diagnosis and guide effective personalized pharmacotherapeutic strategies for addiction, targeted towards the individual's metabolome. The above research areas all have clear aims to improve human health, but the maxim that good translational research must always be underpinned with good basic research is as true for neuropharmacology as it is for any other area of science. Fundamentals include thorough analysis of potential drug targets, including the precise cells and neuronal pathways in which drug targets are expressed and their exact roles in higher brain functions. An example of this is combining behavioural and electrophysiological studies to define the role of Group-II (mGlu2 and mGlu3) metabotropic glutamate receptors in thalamic processing (Copeland et al., 2022). Also essential to good translational neuropharmacology is the development of animal models that accurately recapitulate CNS disorders. Such animals are not only key for the elucidation of neurobiological bases of CNS disorders but also for the development of effective and safe pharmacotherapeutic agents. Animal models for CNS disorders are notorious for their limitations in this respect, which inevitably has had a knock-on effect on drug discovery. One such disorder is autosomal dominant sleep-related hypermotor epilepsy (ADSHE), which was the first distinct genetic epilepsy shown to be caused by nicotinic acetylcholine receptor α4 subunit (CHNRA4) mutation. The creation of robust and reliable genetic rat ADSHE models that harbour pathogenic CHNRA4 mutations will be instrumental in understanding of the neurobiological mechanism underlining ADSHE and the development of effective treatments (Okada, 2022). Finally, a warning for neuropharmacologists: pharmacological interventions are not the only option. Particularly in the case of anxiety, depression and other conditions with a psychiatric origin, changes in lifestyle and behaviour may be sufficient to elicit significant benefits without the risk of adverse effects (Kimura et al., 2022). For example, comorbid depression, anxiety and pain are particularly dependent on the psychosocial environment, since these disorders are linked to stressful events. Furthermore, environment enrichment—physical exercise, supportive therapy, meditation, board games, crafting, etc.—favours individual well-being, boosts overall mood, relieves pain, and helps to build resilience to stress. Importantly, common mechanisms underlying the co-occurrence of pain and depression include mediators of inflammatory and immune functions, like tumour necrosis factor-α (TNFα) and interleukins (IL), which are secreted by activated microglia. Environmental enrichment has been reported to exert numerous benefits, but key among them is modulation of the neuroimmune system, suggesting that positive lifestyle changes may be sufficient to normalize microglial dysfunction towards a homeostatic, neuroprotective state. As mentioned, this issue follows on from a symposium celebrating UK-Brazil research collaborations in neuropharmacology. We hope the articles we have assembled showcase this exciting research field in the manner it deserves and lead to the building of more bridges in neuropharmacology. The authors declare no conflict of interest.