Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders

Abstract

Chronic inflammation of the central nervous system (CNS) is critical to the pathogenesis of neuropsychiatric disorders (NPDs) that affect the global population. Current therapeutics for NPDs are limited to relieving symptoms and induce many adverse effects. Therefore, the discovery of novel therapeutic agents from natural sources is urgently needed. Intriguingly, the immune responses of peripheral organs are closely linked through the molecular communication between resident and blood-borne cellular components, which shape the neuroinflammatory phenotypes of NPDs. Since the gut and spleen are the two largest immunological organs of the body, the brain–gut–microbiome and brain–spleen axes have been implicated in the connection between the CNS and the peripheral immune system. Accordingly, it has been proposed that the local CNS inflammation observed in NPDs is regulated via the manipulation of the systemic immune system by targeting the gut and spleen. Additionally, the complexity of the signalling network underlying the communication between the CNS and the systemic immune system suggests a strong potential for treating NPDs through a polypharmacological approach. The close association between systemic immunity and the homeostasis of the CNS points to the concept of repurposing interventions for systemic immune disorders to treat NPDs. Notably, natural products represent a promising source of such effective compounds due to both their pharmacological potency and safety. This review discusses the complex implications of dysregulated systemic immunity mediated by the brain–spleen and brain–gut–microbiome axes in NPDs, such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and major depressive disorder. In addition, the potential of repurposing natural product-based bioactive compounds for treating NPDs via modulating systemic immune disorders is intensively discussed.

Introduction

Neuropsychiatry is the scientific discipline and medical specialty integrating the study of psychiatric and neurological conditions and focusing on the therapeutic intervention of neurologically based disorders (Lishman, 1992; Martin, 2002; Reynolds 3rd, Lewis, Detre, Schatzberg, & Kupfer, 2009). NPDs are usually associated with dementia and are characterized by the emergence of psychological and behavioural symptoms, such as anxiety, depression, irritability, mood dysregulation, and obsessive-compulsive disorder. These disorders cover a broad spectrum of medical conditions, have a relatively high prevalence, and affect individuals of different ages (Kessler, Chiu, Demler, Merikangas, & Walters, 2005; Kessler et al., 2005). Notably, physical disability and progressive cognitive impairment are the major adverse clinical consequences (Bailey, Neill, & Moran, 2017; Hyman, 2008). Therefore, NPDs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), schizophrenia, and major depressive disorder (MDD), are of particular interest due to their relatively high occurrence and extensive socio-economic impact (Jablensky, 2000; R. C. Kessler, et al., 2003; Qiu, Kivipelto, & von Strauss, 2009; Z. Zhang & Román, 1993).

Nowadays, disease-modifying therapies are not available for NPDs because current therapeutics basically serve as palliative treatments for relieving dementia and other neuropsychiatric symptoms. For example, donepezil, galantamine, rivastigmine, and memantine have been approved for treating neurodegenerative dementia such as AD via targeting cholinergic or glutaminergic pathways to ameliorate the underlying cognitive deficits (Graham, Bonito-Oliva, & Sakmar, 2017; Winblad & Poritis, 1999). Levodopa and/or direct dopamine agonists are effective medications for treating the iconic motor symptoms of PD pathogenesis by activating central dopamine receptors (Connolly & Lang, 2014; Ferreira et al., 2013). Further examples are found in the treatment of NPDs associated with mental illness, including MDD and schizophrenia, in which the serotonin and dopamine systems are targeted by medicinal compounds such as bupropion, duloxetine, haloperidol or perphenazine to induce antidepressant or antipsychotic effects (Kane & Correll, 2010; Madhusoodanan, Alexeenko, Sanders, & Brenner, 2010). Since, these therapeutics for NPDs are symptom-relieving in nature, persistent drug exposure in patients becomes unavoidable and leads to the development of side effects (Demyttenaere & Jaspers, 2008; Marder et al., 2003; Marsden & Parkes, 1976; Rockwood, Mintzer, Truyen, Wessel, & Wilkinson, 2001). Accordingly, there is a pressing need to identify novel therapeutic compounds that can potentially interfere with the onset or pathogenesis of NPDs. However, due to the multifactorial aetiology of NPDs, the molecular targets (Roth, Sheffler, & Potkin, 2003), biomarkers (H. M. Lee & Kim, 2016) , and pharmacological therapies (H. M. Lee & Kim, 2016) currently used to treat NPDs are limited. Therefore, elucidating the pathophysiological mechanisms shared among the different NPDs may facilitate the development of specific therapeutic compounds to interfere with the complex pathogenetic pathways of NPDs in a polypharmacological approach.

Neuroinflammation have been revealed in most of these diseases such as AD (Lopez-Picon et al., 2018; Unterberger et al., 2006), PD (Shahnawaz et al., 2017; Tiwari & Pal, 2017), Schizophrenia (Fournier et al., 2017; Lopez-Gonzalez et al., 2019; Tsai et al., 2018), and MDD (Kim, Na, Myint, & Leonard, 2016; Meyer, 2017). Intriguingly, an increasing number of findings has suggested a close mechanistic connection between the neuroimmune system and systemic immunity, which are also involved in the pathogenesis of different diseases associated with the CNS (Cryan & Dinan, 2012; Liblau, Gonzalez-Dunia, Wiendl, & Zipp, 2013; Marchi, Granata, & Janigro, 2014; Qureshi & Mehler, 2013). Therefore, it is tempting to question whether the pathological progression in the brains of NPD patients can be managed by targeting systemic immunohomeostasis. As such, this article aims to rationalize the idea of manipulating local inflammation in the diseased brain via pharmacological intervention in the systemic immune system. The pathways involved in brain-periphery crosstalk mediated through the brain–spleen and brain–gut–microbiome axes are the key facets of this concept. Owing to the mechanistic complexity of NPDs, the use of multi-target polypharmacological herbal chemicals appears to be a better therapeutic approach than the use of chemical drugs that act on a single target. Over the past two decades, the use of polypharmacological approaches for treating complex diseases such as cancer and cardiovascular diseases has been of rising interest (Anighoro, Bajorath, & Rastelli, 2014; Proschak, Stark, & Merk, 2019). Accordingly, both the effects of the altered integrity of the brain–spleen and brain–gut–microbiome axes in the neuroinflammatory process associated with NPDs and the repurposing of drugs that conventionally target immunological disorders for the treatment of neuroinflammation are important topics of focus.