Ilex kudingcha C.J. Tseng Mitigates Phenotypic Characteristics of Human Autism Spectrum Disorders in a Drosophila Melanogaster Rugose Mutant

Neurochem Res. 2021 Aug;46(8):1995-2007. doi: 10.1007/s11064-021-03337-7. Epub 2021 May 5.


Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Tseng is a nootropic botanical used in Asia for neuroprotection and improvement of cognition. This study establishes that a chemically characterized extract from IK (IKE) mitigates behavioral traits in the Drosophila melanogaster rugose mutant, whose traits resemble human ASD, and examines possible mechanisms. IKE treatment significantly ameliorated deficits in social interaction, short-term memory, and locomotor activity in Drosophila rugose, and significantly increased synaptic bouton number of size more than 2 μm2 in the neuromuscular junctions (NMJs) of Drosophila rugose. To clarify mechanism(s) of IKE action, methylphenidate (MPH), a dopamine transporter inhibitor, was included as a reference drug in the behavioral assays: MPH significantly improved social interaction and short-term memory deficit in Drosophila rugose; administration of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist sulpiride reversed the ameliorative effects of both MPH and IKE on the social interaction deficits of Drosophila rugose. To extend analysis of IKE treatment to the vertebrate central nervous system, ASD-associated gene expression in mouse hippocampus was studied by RNA-seq: IKE treatment altered the expression of genes coding phosphoinositide 3-kinases/protein kinase B (PI3K-Akt), proteins in glutamatergic, dopaminergic, serotonergic, and GABAergic synapses, cAMP response element-binding protein (CREB), and RNA transporter proteins. These results provide a foundation for further analysis of IKE as a candidate for treatment of some forms of ASD.

Keywords: Autism spectrum disorder; Dopaminergic synapsesa; Drosophila melanogaster rugose; Ilex kudingcha.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / drug therapy*
  • Autism Spectrum Disorder / metabolism
  • Circadian Rhythm / drug effects
  • Drosophila melanogaster / genetics
  • Gene Expression / drug effects
  • Hippocampus / metabolism
  • Humans
  • Ilex / chemistry
  • Locomotion / drug effects
  • Memory, Short-Term / drug effects
  • Methylphenidate / therapeutic use
  • Nootropic Agents / therapeutic use*
  • Phenotype
  • Plant Extracts / therapeutic use*
  • Plant Leaves / chemistry
  • Presynaptic Terminals / drug effects
  • Social Interaction / drug effects
  • Vietnam


  • Nootropic Agents
  • Plant Extracts
  • Methylphenidate