Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD? Item Type Article;Other Authors Eissa, Nermin;Sadeq, Adel;Sasse, Astrid;Sadek, Bassem DOI 10.3389/fphar.2020.00886 Journal Frontiers in pharmacology Rights Copyright © 2020 Eissa, Sadeq, Sasse and Sadek. Download date 01/10/2021 00:32:48 Link to Item http://hdl.handle.net/10147/629973 Find this and similar works at - http://www.lenus.ie/hse REVIEW published: 16 June 2020 doi: 10.3389/fphar.2020.00886 Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD? Nermin Eissa 1,2, Adel Sadeq 3, Astrid Sasse 4 and Bassem Sadek 1,2* 1 Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, 2 Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, 3 College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates, 4 School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, University of Dublin, Dublin, Ireland Many behavioral and psychological symptoms of dementia (BPSD) share similarities in executive functioning and communication deficits with those described in several neuropsychiatric disorders, including Alzheimer’s disease (AD), epilepsy, schizophrenia Edited by: (SCH), and autism spectrum disorder (ASD). Numerous studies over the last four decades Bjorn Johansson, have documented altered neuroinflammation among individuals diagnosed with ASD. The Karolinska Institutet (KI), Sweden purpose of this review is to examine the hypothesis that central histamine (HA) plays a Reviewed by: Chieh-Hsin Lin, significant role in the regulation of neuroinflammatory processes of microglia functions in Kaohsiung Chang Gung Memorial numerous neuropsychiatric diseases, i.e., ASD, AD, SCH, and BPSD. In addition, this Hospital, Taiwan Savina Apolloni, review summarizes the latest preclinical and clinical results that support the relevance of University of Rome Tor Vergata, Italy histamine H1-, H2-, and H3-receptor antagonists for the potential clinical use in ASD, *Correspondence: SCH, AD, epilepsy, and BPSD, based on the substantial symptomatic overlap between Bassem Sadek these disorders with regards to cognitive dysfunction. The review focuses on the [email protected] histaminergic neurotransmission as relevant in these brain disorders, as well as the Specialty section: effects of a variety of H3R antagonists in animal models and in clinical studies. This article was submitted to Neuropharmacology, Keywords: behavioral and psychological symptoms of dementia, Alzheimer’s disease, schizophrenia, autism a section of the journal spectrum disorder, cytokines, neuroinflammation, central histamine receptors, H3R antagonists Frontiers in Pharmacology Received: 18 December 2019 Accepted: 29 May 2020 Abbreviations: ASD, Autism Spectrum Disorder; AbP, Amyloid beta peptide; ACh, Acetylcholine; AChE, Acetylcholine Published: 16 June 2020 esterase; ACEI, Acetylcholine esterase inhibitor; AD Alzheimer’s disease; ADHD, Attention deficit hyperactivity disorder; APP, Amyloid protein precursor; BPSD, Behavioral and Psychological Symptoms of Dementia; CNS, Central Nervous System; Citation: COX, Cyclooxygenase; H3R, Histamine H3 Receptor; HA, Histamine; GSK-3b, Glycogen synthase kinase 3 beta; GM, Grey Eissa N, Sadeq A, Sasse A and matter; DSM, Diagnostic and Statistical Manual of Mental Disorders; EMA, European Medicines Agency; FDA, Food and Sadek B (2020) Role of Drug Administration; H O , Hydrogen peroxide; HDC, Histidine Decarboxylase; HR, Histamine Receptor; HNMT, fl 2 2 Neuroin ammation in Autism Histamine Nmethyl Transferase; HS, Histaminergic System; IL, Interleukin; IFN-g, interferon gamma; LPS, Spectrum Disorder and the Lipopolysaccharide; MCI, Mild cognitive impairment; NF-kB, Nuclear Factor kappalight-chain-enhancer of activated B Emergence of Brain Histaminergic cells; iNOS, Inducible nitric oxide synthase; NO, Nitric Oxide; NRXN, Neurexin; NMDA, NMethyl-D-aspartate; PCP, ’ System. Lessons Also for BPSD? Phencyclidine; PD, Parkinson s disease; PGE2, Prostaglandin E2; ROS, Reactive Oxygen Species; SCH, Schizophrenia; TNF-a, Front. Pharmacol. 11:886. Tumor necrosis factor alpha; TS, Tourette syndrome; SOD, Superoxide dismutase 1; TGF-b, Transforming growth factor beta; doi: 10.3389/fphar.2020.00886 ToM, Theory of Mind; VPA, Valproic Acid; i.p., Intraperitoneally; WM, White matter. Frontiers in Pharmacology | www.frontiersin.org 1 June 2020 | Volume 11 | Article 886 Eissa et al. Brain Histamine and Neuroinflammation INTRODUCTION worldwide, and is expected to rise (Arvidsson et al., 2018). Despite the high prevalence rate, the etiology and pathogenesis ASD as a Prototype for Neuropsychiatric of this disorder are still largely unknown and remain a matter of Disorders speculation. The lack of a specific etiologic diagnosis can be Alzheimer’s disease (AD) patients are often found to show attributed to limited human brain accessibility and the apathy, depression, eating, and sleeping disorders, aggressive complexity of the neurobiology of its activity (Nestler and behavior, as well as other non-cognitive symptoms (Selles Hyman, 2010).ASDisaheterogeneousgroupof et al., 2018). These symptoms are usually associated with AD neurobehavioral abnormalities with different recognized pathology but are often neglected as part of disease progression genetic and environmental origins. Genetic and environmental due to the early and more profound disturbances of memory factors are strongly suggested to be involved in incidence of ASD centers in the hippocampus and entorhinal cortex. AD comprises (Baronio et al., 2015). Additionally, the heterogeneous behavioral up to 80% of all dementias. Behavioral and psychological symptoms and neuropsychiatric comorbidities in autistic symptoms of dementia (BPSD) in AD are known recently to children make it difficult to decipher the pathophysiology of correlate with gray matter (GM) atrophy and, also with white this disorder, and consequently to develop a fundamental matter (WM) damage. WM damage and its relationship with therapeutic approach to ASD. Therefore, subgrouping of ASD GM atrophy are reported in AD (Makovac et al., 2016). children with shared symptoms and shared molecular changes Additionally, Sokol et al. reported that Amyloid-b protein into several categories and observing their response to precursor (bAPP) and its metabolites to be dysregulated not intervention is essential (James et al., 2009). Pharmacological only in AD, but also in Autism spectrum disorder (ASD), and treatments addressing core symptoms in ASD still remain that the secreted variant of APP may lead to increased brain challenging. Despite expanding awareness and advances in WM. WM structure is dynamic and is essential to cognitive early age, efficacious reversal of these persistent autistic function (Courchesne et al., 2003; Dawson et al., 2007). WM is symptoms is not yet achieved. To date, risperidone and largely composed of glia including microglia and it was proposed aripiprazole are the only two ASD-specific drugs approved by that neuroinflammation along with increased myelination, may the US Food and Drug Administration (FDA) for improving contribute more to the WM enlargement in ASD (Herbert, 2005; behavioral ASD associated symptoms, such as irritability Fields, 2008; Aoki et al., 2017; Sokol et al., 2019). (Matson et al., 2011). There is lack of effective therapeutic Neuroinflammation appears to be similar in ASD and AD interventions that address ASD hallmark symptoms (Sheldrick (Herbert, 2005), hence, applying known pathways in AD to and Carter, 2018; Xu et al., 2018). Pharmacotherapeutic options ASD as proposed, should provide drug targets for ASD. that are currently used target accompanying symptoms in ASD, Therefore, knowledge from better developed field as AD opens but are not disease-modifying and do not provide symptomatic the door to better understand ASD. control of core symptoms (Wong and Smith, 2006; Hanson et al., Interestingly, BPSD are present in almost 90% of patients 2007). These accompanying physiological and psychiatric diagnosed with AD, characterized as a disorder of heterogeneous symptoms of ASD include attention deficit, anxiety, irritability, degenerative symptoms with memory and cognitive deficits hyperactivity, self-injuries, aggression, in addition to sleep, considered as the core symptoms across multiple symptom sensory, and gastrointestinal disturbances (Lai et al., 2014; domains (Chakraborty et al., 2019). Many BPSD share Summers et al., 2017). Psychiatric drugs are frequently used for similarities with symptoms observed in AD, schizophrenia treating these symptoms in autistic children (Findling, 2005). (SCH), and ASD including depression, anxiety, executive Despite the outstanding research that has been accomplished on functioning deficits, and communication deficits (Wallace ASD, complete and effective treatments targeting ASD core et al., 2016; Rhodus et al., 2019). ASD is a biologically based symptoms has been challenging and not yet achieved, as persistent neurodevelopmental disorder of which the core mentioned earlier. Therefore, significant progress toward the symptoms include impaired social interaction and repetitive goal of identifying treatments for improving and potentially even behaviors with restricted interests (Baronio et al., 2015). The curing core