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In This Article
  Introduction
  Newer Targets
  Receptors Targets
  Targeting Pathways
   Targeting Centra...
   References
   Article Figures

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 Table of Contents    
POTENTIAL PHARMACOLOGICAL TARGETS
Year : 2019  |  Volume : 51  |  Issue : 4  |  Page : 284-286
 

Newer potential pharmacological targets for autism spectrum disorder


Department of Pharmacology, PGIMER, Chandigarh, India

Date of Submission19-Aug-2019
Date of Acceptance19-Aug-2019
Date of Web Publication13-Sep-2019

Correspondence Address:
Dr. Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_518_19

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How to cite this article:
Jain R A, Prakash A, Medhi B. Newer potential pharmacological targets for autism spectrum disorder. Indian J Pharmacol 2019;51:284-6

How to cite this URL:
Jain R A, Prakash A, Medhi B. Newer potential pharmacological targets for autism spectrum disorder. Indian J Pharmacol [serial online] 2019 [cited 2019 Oct 15];51:284-6. Available from: http://www.ijp-online.com/text.asp?2019/51/4/284/266823





  Introduction Top


Autism is a cluster of heterogeneous disorders which are neurodevelopmental and are distinctive by initial difficulties in social life, communication among individuals, restrictive/repetitive behavior, and interests. The pathophysiology behind autism is still complex, and no single etiological and pathophysiological mechanism is involved. There are many different etiologies behind autism spectrum disorder (ASD).

There are only two United States Food and Drug Administration (US-FDA)-approved pharmacological treatments that are available for ASD, i.e., aripiprazole and risperidone. The other pharmacologic interventions for any comorbid condition are alpha-2 adrenergic receptor agonists, atypical antipsychotic drugs, psychostimulants, cholinesterase enzyme inhibitors, antidepressants, antiepileptic mood stabilizers, and NMDA receptor antagonists.[1] These are antipsychotic drugs which are used for one of the symptoms of autism, i.e., irritability and repetitive behavior along with that these drugs have side effects including sedation and weight gain. There is an urgent need of cure for this spectrum disorder.[2]

Therapies for ASD as nonpharmacological treatment include cognitive-behavioral therapy, oxytocin and vasopressin, complementary and integrative health, social-behavioral therapy, music therapy, omega-3, vitamins and herbal medicine, and also neuromodulatory effects of music.[1]


  Newer Targets Top


The newer targets for ASD may involve the histamine receptor antagonist, particularly H3 receptor and acetylcholine esterase inhibitor.[3] In another study by Rodriguez and Kern, 2011 and Takano, 2015, they suggested that the role of microglial activation and neuroinflammation are also associated with ASD.[4],[5] Increased nitric oxide production decreases the activity of natural killer cells which may also be a beneficial target in autistic children.[6],[7] Developmental and social impairment has been seen with increased T-cell activation and increased levels of pro-inflammatory markers.[8] Elevated levels of various inflammatory markers such as interleukin (IL)-1β, IL-5, IL-6, IL-8, IL-12, IL-13, IL-17, IL-23, and IL-1RA, and tumor necrosis factor-α have been found in the postnatal period of many individuals.[9] The above elevated levels have displayed increased stereotypic behavior and memory impairment. The monogenetic ASDs are tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Rett syndrome (RTT) [Figure 1]. In TSC, the gene TSC1 or TSC2 is mutated which encrypts hamartin and tuberin. In FXS, FMR1 gene is silenced which encodes FMRP. In RTT, X-linked MECP2 gene is mutated which binds to DNA's methyl group that acts as a transcriptional regulator.
Figure 1: Pharmacological targets for ASD

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  Receptors Targets Top


The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor [AMPAR] or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the [Figure 1] central nervous system (CNS). In autistic patients hampered with AMPA receptors have exhibit increased expression of GluA1, copy number variations in genetic loci of AMPAR along with that GRIA2 factor deletion has been associated.[10] The autistic patients who possess pathophysiology of glutamatergic neurotransmission i.e., hampering of Group II metabotropic glutamate receptor, modulation of this receptor could improve the patient quality of life, particularly individuals who have alteration in the Glutamatergic levels.[11] Additionally, in case of mGlu5 receptor hindered individuals, well-being of these patients can be improved by antagonizing mGlu5 receptor and altering the levels of this receptor. Ionotropic glutamate NMDA receptor-modulation or blockade of this receptor could ameliorate the autistic symptoms. GABA imbalance of GABA a/b causes neuronal postsynaptic excitation to be increased. Hence, by increasing the levels of GABA could be beneficial for ASD.


  Targeting Pathways Top


PI3K/mTOR pathway–TSC1, TSC2, FMRP gene mutation [Figure 1] causes imbalance of PI3K pathway which increases the activity of mTOR and causes autistic symptoms, so modulation in this pathway could provide beneficial clinical outcome. Dendritic spine–synapse function and spine morphology are linked with each other. Spine density and its morphological abnormalities cause autistic symptoms. Insulin-like growth factor-1 (IGF-1) causes alteration in PI3K/Akt, Ras-Raf-MAP, mTOR, GSK3 β, β-catenin, ERK1/2, and p38 MAPK. SHANK proteins' - mutations of SHANK3 gene and SHANK proteins' - dysregulation cause NMDA, AMPARs alterations which leads to excitatory/inhibitory imbalance (E/I imbalance). E/I balance-increased glutamate or E/I balance-decreased GABA activity causes impaired synaptic plasticity which leads to E/I imbalance. Synaptic dysfunction – Disruption in synaptic function and synaptic plasticity can lead to remodelling in neuronal function. GSK3 – Hyperphosphorylation of GSK3β causes β-catenin to degrade quickly in the nucleus in turn β-catenin is not available for the transcription of protein such as TCF/LEF which has found to causes autism.


  Targeting Central Nervous System Top


Serotonin neurotransmission system alterations in 5-HT neurotransmitter [Figure 1] cause autistic symptoms. Cholinergic system cholinergic receptors and α4 β2, α7 abnormalities cause autistic symptoms. Oxytocin system variation in oxytocin [Figure 1] levels causes communication and social disturbances. As said above in neuroinflammation, autoimmune disorders and infections from bacteria and such other factors cause neuroinflammation [Figure 1], and it is majorly involved in ASD individuals.

Therefore, there is a crucial need of an ideal animal model which represents the above described pathophysiology from clinical to non-clinical conditions that can be evaluated by replicative batteries of behavioral changes during the development phase as well as substantiating them at different cellular, molecular levels, histological and immunohistochemical confirmations and harmonizing them for their clinical outcome.[12]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kumar B, Prakash A, Sewal RK, Medhi B, Modi M. Drug therapy in autism: A present and future perspective. Pharmacol Rep 2012;64:1291-304.  Back to cited text no. 1
    
2.
Sharma SR, Gonda X, Tarazi FI. Autism spectrum disorder: Classification, diagnosis and therapy. Pharmacol Ther 2018;190:91-104.  Back to cited text no. 2
    
3.
Eissa N, Azimullah S, Jayaprakash P, Jayaraj RL, Reiner D, Ojha SK, et al. The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 ameliorates stereotyped repetitive behavior and neuroinflammation in sodium valproate induced autism in mice. Chem Biol Interact 2019;312:108775.  Back to cited text no. 3
    
4.
Rodriguez JI, Kern JK. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol 2011;7:205-13.  Back to cited text no. 4
    
5.
Takano T. Role of microglia in autism: Recent advances. Dev Neurosci 2015;37:195-202.  Back to cited text no. 5
    
6.
Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen RL, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun 2009;23:124-33.  Back to cited text no. 6
    
7.
Warren RP, Foster A, Margaretten NC. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry 1987;26:333-5.  Back to cited text no. 7
    
8.
Careaga M, Rogers S, Hansen RL, Amaral DG, Van de Water J, Ashwood P. Immune endophenotypes in children with autism spectrum disorder. Biol Psychiatry 2017;81:434-41.  Back to cited text no. 8
    
9.
Masi A, Glozier N, Dale R, Guastella AJ. The immune system, cytokines, and biomarkers in autism spectrum disorder. Neurosci Bull 2017;33:194-204.  Back to cited text no. 9
    
10.
Kim JW, Park K, Kang RJ, Gonzales EL, Kim DG, Oh HA, et al. Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism. Neuropsychopharmacology 2019;44:314-23.  Back to cited text no. 10
    
11.
Fung LK, Hardan AY. Developing medications targeting glutamatergic dysfunction in autism: Progress to date. CNS Drugs 2015;29:453-63.  Back to cited text no. 11
    
12.
Ruhela RK, Prakash A, Medhi B. An urgent need for experimental animal model of autism in drug development. Ann Neurosci 2015;22:44-9.  Back to cited text no. 12
    


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