Therapeutic effects of Lactobacillus rhamnosus and/or thymol against neurotoxicity in propionic acid (PA)-induced autistic rats: Insights for the role of Nrf2/HO-1, Wnt3/β-Catenin/GSK3β BDNF/p-TrkB/CREB, pI3K/Akt/mTOR, AMPK/SIRT-1 and PERK/CHOP/Bcl-2 pathways

Hoda A. Salem^1*Nermin Rizk¹Moustafa H Abdelsalam¹Rehab Ahmed¹Hebatallah Atteia¹Ahmed M.E. Hamdan¹Areej A. Alghamdi¹Manar A. Alghusn¹Renad A. Alatawi¹Rawan A. Atallah¹Maryam M Alfuhaymani¹Hatun A Alqahtani¹Karema Abu-Elfotuh²

• ¹University of Tabuk, Tabuk, Saudi Arabia
• ²Al-Azhar University, Nasr City, Egypt

Background: Autism spectrum disorder (ASD) is a neurodevelopmental diseases characterized by repetitive behaviors and a lack of social communication. Role of probiotics and/or phytochemicals as treatment options are still under development. Objective: This study aimed to evaluate the associated molecular pathways and explore the impact of Lactobacillus rhamnosus (L. rhamnosus) and/or thymol (Thy) on propionic acid (PA)-induced ASD rats. Methods: Fifty three-weeks old male albino rat pups were randomly distributed into five groups. The control group, PA-induced ASD group; PA (250 mg/kg, p.o.) for three days and the three other groups administered PA; PA (250 mg/kg, p.o.) for three days with either L. rhamnosus (1× 10^6 CFU/day, p.o), Thy (30 mg/kg/day, p.o), or both. Brain tissues were removed for biochemical, histological and immunohistochemical studies followed behavioral evaluations. Results: In contrast to the PA-intoxicated group, treatment by L. rhamnosus and/or Thy significantly improved the neurobehavioral deficits compared to the autistic group in tests including memory consolidation, learning capacity, attention, spatial memory, locomotor activity and collection of contextual information compared to PA-treated group. Along with histopathological findings, L. rhamnosus and/or Thy also demonstrated notable ameliorative effects for PA-induced abnormalities in brain neurotransmeters, oxidative stress, inflammation, apoptosis, and Endoplasmic Reticulum (ER) stress and autophagy biomarkers. Furthermore, using L. rhamnosus and/or Thy improved the previous abnormalities regarding the tested biomarkers as well as modulating pathways associated with a significant upregulation of BDNF, TrkB, CREB, Nrf2 and HO-1 content and a downregulation of TLR4/NF-κB-arbitrated neuroinflammation which lead to great improvements of ASD symptoms. Conclusion: Our results suggests that L. rhamnosus and/or Thy have good therapeutic potentials in alleviating biochemical and behavioral deficits in a PA-induced autism, possibly by halting apoptosis, inflammation and endoplasmic reticulum stress, along with inducing autophagy, via improving different biomarkers and modulation pathways such as: Wnt3/β-Catenin/GSK3β, pI3K/p-Akt/mTOR, BDNF/p-TrkB/CREB.