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April 13, 2023

Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is becoming a major threat, a large public health challenge, and the most common ongoing developing disorder in public health. In the United Arab Emirates (UAE), the number of children diagnosed with ASD has rocketed over the last decade. Statistics indicate that ASD affects one in 146 births in the UAE, and cases appear to be rising worldwide. In the USA, the number of children diagnosed with the condition has elevated to one in 36 diagnosed with autism. That rate compares with one in 44 identified with autism in 2018, according to a recent report from the USA’s Center for Disease Control and Prevention.

As more children are diagnosed in the UAE and worldwide, the financial toll on families already struggling emotionally with the diagnosis is huge. Consequently, there is an urgent need for innovative interdisciplinary studies to discover new pathways to understand the pathophysiology of ASD better, ultimately leading to a new class of drugs targeting the core behaviors of ASD. By targeting new altered pathways in ASD, we expect a promising new pharmacological intervention through modulating this disruption, hence preventing, or at least improving, the symptomatic core autistic features selectively.

Hands of a child diagnosed with Autism Spectrum Disorder playing with puzzles

Challenges of Autism Spectrum Disorder

Children with ASD face a variety of challenges, and due to the scarce availability of potent medications, raising a child diagnosed with ASD negatively impacts parents and the family. ASD is a neurodevelopmental disorder characterized by core symptoms of impairments in social interactions and communication, restricted/repetitive, and stereotyped behavior (1). The reported increase in the prevalence of ASD has attracted public attention and become a high priority for scientists and healthcare providers (2). Despite its large population prevalence, the pathophysiology of ASD is still poorly understood, and this can be attributed to challenges in identifying the complex involvement of several clinical and behavioral symptoms, making clinically accessible specific treatments for ASD often less effective. To date, there are no efficient therapeutic interventions that target the core symptoms of ASD, making developing newer therapeutics an important area of research.

Histamine and Autism Spectrum Disorder

The histaminergic system (HS) in the central nervous system (CNS) consists of cell bodies of histamine neurons confined in one area of the posterior hypothalamus called the tuberomammillary nucleus (TMN), and sends projections to the spinal cord, brain stem, and many telencephalic brain areas (3). Hence, brain histamine has been suggested to be a regulator of the activity of the “whole brain” (4). The involvement of histamine receptors (HRs) has long been confirmed in cognitive functions, notably of histamine 3 receptors (H3Rs), which are predominantly and heterogeneously expressed in the CNS (3, 5). Exploring the potential role of histamine H3R antagonist in a number of CNS diseases like Alzheimer’s disease, epilepsy, attention deficit hyperactivity disorder (ADHD), narcolepsy (6, 7), schizophrenia (SCH)  and recently in Tourette syndrome and ASD (8), suggested that H3R antagonists are potential therapeutics for the treatment of different brain disorders. Consequently, mounting evidence revealed that ligands targeting central H3R are considered potential therapeutic agents for the treatment of different brain disorders associated with cognitive impairments. H3Rs are mainly expressed in the basal ganglia, globus pallidus, hippocampus, and cortex in humans (9). Accordingly, the brain histaminergic system and HRs have been implicated in many brain disorders, suggesting that it may have a critical role in their pathophysiology. The implication of HS in many neurological disorders that share comorbidity with ASD may add a new therapeutic management strategy. Genetic and symptomatic overlap between SCH and ASD suggests that the histaminergic system and HRs are also implicated in ASD (10, 11). Previous observation showed that ciproxifan (imidazole-based H3R antagonist) was able to improve sociability and stereotypy in an animal model of valproic acid (VPA)-induced ASD (1, 12), demonstrating the potential role of HRs and H3R antagonists in treating ASD core symptoms. Recent studies revealed that simultaneous targeting of the CNS histaminergic and dopaminergic neurotransmissions is highly beneficial for the palliation of several ASD-like features, namely ASD like social deficits and repetitive/compulsive behaviors (13, 14) . Further large-scale controlled studies will be needed to confirm the findings. Deciphering the pathophysiology of ASD and introducing new pharmacological therapies to manage autistic core symptoms is crucial to help suffering patients and minimize the burden on their families.

Nermin Eissa, PhD
 Assistant Professor of Biomedical Sciences
Biomedical Sciences Department
College of Health Sciences

References

  1. Baronio D, Castro K, Gonchoroski T, de Melo GM, Nunes GD, Bambini-Junior V, et al. Effects of an H3R antagonist on the animal model of autism induced by prenatal exposure to valproic acid. PLoS One. 2015;10(1):e0116363.
  2. Arvidsson O, Gillberg C, Lichtenstein P, Lundstrom S. Secular changes in the symptom level of clinically diagnosed autism. J Child Psychol Psychiatry. 2018;59(7):744-51.
  3. Sadek B, Saad A, Sadeq A, Jalal F, Stark H. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behavioural Brain Research. 2016;312:415-30.
  4. Wada H, Inagaki N, Yamatodani A, Watanabe T. Is the histaminergic neuron system a regulatory center for whole-brain activity? Trends in neurosciences. 1991;14(9):415-8.
  5. Sadek B, Stark H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology. 2016;106:56-73.
  6. Kasteleijn-Nolst Trenite D, Parain D, Genton P, Masnou P, Schwartz JC, Hirsch E. Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model. Epilepsy & behavior : E&B. 2013;28(1):66-70.
  7. Baronio D, Gonchoroski T, Castro K, Zanatta G, Gottfried C, Riesgo R. Histaminergic system in brain disorders: lessons from the translational approach and future perspectives. Ann Gen Psychiatry. 2014;13(1):34.
  8. Rapanelli M, Pittenger C. Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions. Neuropharmacology. 2016;106(Supplement C):85-90.
  9. Martinez-Mir MI, Pollard H, Moreau J, Arrang JM, Ruat M, Traiffort E, et al. Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain research. 1990;526(2):322-7.
  10. Couture SM, Penn DL, Roberts DL. The functional significance of social cognition in schizophrenia: a review. Schizophrenia bulletin. 2006;32 Suppl 1:S44-63.
  11. Meyer U, Feldon J, Dammann O. Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatric research. 2011;69(5 Pt 2):26r-33r.
  12. Eissa N, Jayaprakash P, Azimullah S, Ojha SK, Al-Houqani M, Jalal FY, et al. The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism. Sci Rep. 2018;8(1):13077.
  13. Venkatachalam K, Eissa N, Awad MA, Jayaprakash P, Zhong S, Stolting F, et al. The histamine H3R and dopamine D2R/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf/J mice by multiple actions. Biomed Pharmacother. 2021;138:111517.
  14. Eissa N, Venkatachalam K, Jayaprakash P, Yuvaraju P, Falkenstein M, Stark H, et al. Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism. Pharmaceuticals. 2022;15(8):929.

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