Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by social and communication deficits as well as repetitive behaviour. Several studies have found that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays a significant role in autism pathogenesis. Overexpression of the PI3K/AKT/mTOR signalling pathway causes neurological disorders by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a naturally occurring chemical obtained from the plant Rheum palmatum. This study aimed to examine the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological alterations in ICV-PPA induced experimental model of autism in adult rats. The effects of ICV-PPA on PI3K/AKT/mTOR downregulation in the brain were studied in autism-like rats. Furthermore, we investigated how CPH affected myelin basic protein (MBP) levels in rat brain homogenate and apoptotic biomarkers such as caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were tested for behavioural abnormalities such as neuromuscular dysfunction using an actophotometer, motor coordination using a beam crossing task (BCT), depressive behaviour using a forced swim test (FST), cognitive deficiency, and memory consolidation using a Morris water maze (MWM) task. In PPA-treated rats, prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms. Furthermore, in rat brain homogenates, blood plasma, and CSF samples, cellular, molecular, and cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators were investigated. The recent findings imply that CPH also restores abnormal neurochemical levels and may prevent autism-like gross pathological alterations, such as demyelination volume, in the rat brain.
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Abbreviations
- CNS:
-
Central nervous system
- mTOR:
-
Mammalian target of rapamycin
- PI3K:
-
Phosphoinositide 3-kinase
- CPH:
-
Chrysophanol
- AKT:
-
Protein kinase B (PKB)
- ASD:
-
Autism spectrum disorder
- AD:
-
Alzheimer’s disease
- ASD:
-
Autism spectrum disorder
- BBB:
-
Blood brain barrier
- DA:
-
Dopamine
- ICV:
-
Intracerebroventicular
- PD:
-
Parkinson’s disease
- PPA:
-
Propionic acid
- SOD:
-
Superoxide dismutase
- MDA:
-
Malondialdehyde
- TNF:
-
Tumor necrosis factor
- GSH:
-
Glutathione
- LDH:
-
Lactate dehydrogenase
- IL-1β:
-
Interleukin-1β
- HPLC:
-
High performance liquid chromatography
- AchE:
-
Acetylcholinesterase
- Ach:
-
Acetylcholine
- TSTQ:
-
Time spent in target quadrant
- ELT:
-
Escape latency time
- MWM:
-
Morris water maze
- BCT:
-
Beam crossing task
- FST:
-
Forced swim test
- MBP:
-
Myelin basic protein
- AD:
-
Alzheimer’s disease
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Acknowledgments
The authors express their gratitude to Chairman, Mr. Parveen Garg, and Director, Dr. G.D.Gupta, ISF College of Pharmacy, Moga (Punjab), India, for their excellent vision and support.
Funding
This work was supported by institutional grants from the Institutional Animal Ethics Committee (IAEC) with registration no. 816/PO/ReBiBt/S/04/CPCSEA as protocol no. IAEC/CPCSEA/Meeting No: 27/2020/Protocol No. 454approved by RAB Committee, ISFCP, Moga, Punjab, India.
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Ms. Aarti Sharma (First Author).
M. Pharm, Neuropharmacology Division, Department of Pharmacology.
ISF College of Pharmacy, Moga, Punjab, India.
Contribution: Thesis research work, Performed experimental animal studies.
Ms. Sonalika Bhalla (Second author).
M. Pharm, Neuropharmacology Division, Department of Pharmacology.
ISF College of Pharmacy, Moga, Punjab, India.
Contribution: Revision of entire research manuscript, editing.
Dr. Sidharth Mehan (Corresponding Author* and Third Author).
PhD, M. Pharm, Neuropharmacology Division, Department of Pharmacology.
ISF College of Pharmacy, Moga, Punjab, India.
Contribution: Original research hypothesis, guide, and compilation of all manuscript data.
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Sharma, A., Bhalla, S. & Mehan, S. PI3K/AKT/mTOR signalling inhibitor chrysophanol ameliorates neurobehavioural and neurochemical defects in propionic acid-induced experimental model of autism in adult rats. Metab Brain Dis 37, 1909–1929 (2022). https://doi.org/10.1007/s11011-022-01026-0
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DOI: https://doi.org/10.1007/s11011-022-01026-0