1. Introduction
utism Spectrum Disorders (ASD) is an advanced neurological disorder characterized by symptoms such as impaired social interaction, communication, and cognition by the presence of repetitive patterns of behavior [1]. The main cause of this disorder is the interaction between genetic and environmental factors. Several studies have shown the increased oxidative stress in ASD patients that may contribute to the development of this disorder [2]. Although Rhus Coriaria L. (Sumac) contains compounds with antioxidant and anti-inflammatory properties, the therapeutic use of its extract is limited due to its low bioavailability and biological absorption [4, 3]. Various approaches including the use of natural compounds in the form of nanoparticles such as nano-phytosome have been proposed to improve its effectiveness [5]. This study aims to compare the neuroprotective effects of sumac extract and its nano-phytosome form on memory impairment and oxidative stress in the hippocampus of rats with ASD. 
2. Materials and Methods
 In this experimental study, pregnant female rats were divided into healthy and patient groups. In the patient group, 500 mg/kg body weight valproic acid (VPA) was injected intraperitoneally on day 12.5 of pregnancy. Male rats born in the healthy group were further divided into two healthy control and positive control groups, and those in the patient group were divided into two treatment groups of Sumac Extract (SE, n=6) and Sumac Nano-Phytosome (SNP, n=6) 21 days after birth. The control groups received only saline, while treatment groups received SE and SNP (40 mg/kg/PO) for 4 weeks. Novel Object Recognition (NOR) test was performed to assess recognition memory of rats on day 49 after birth. The NOR task was performed in the Plexiglas open box (40×40×60 cm) with sawdust covering the floor. The Discrimination Index (DI) was defined as the difference between the time spent exploring novel and familiar objects and the total exploring time [6]. Finally, total Antioxidant Capacity (TAC), Glutathione Peroxidase (GPx), Glutathione Reductase (GRx) and Catalase (CAT) levels were measured. The CAT, GPx, GRx, and TAC levels were assessed using the methods proposed by Aebi [7], Rotruck [8], Pinto [9], and Benzie [10], respectively. All statistical analyses were carried out in GraphPad Prism version 8.0.2 software. The data were expressed as Mean±Standard Deviation (SD). Comparisons were performed using one-way ANOVA followed by Tukey’s test. P<0.05 was considered as the significance level.
3. Results
The induction of ASD model resulted in a significant decrease in DI in the patient group compared to the control group (P<0.001). Treatment with SE and SNP significantly increased the DI during NOR test. The levels of CAT, GPx, GRx, and TAC in the patient group were significantly decreased compared to the control group (P<0.001). Treatment with SE significantly increased the levels of CAT (P<0.05), GPx (P<0.001), and GRx (P<0.01), while treatment with SNP significantly increased CAT (P<0.05), GPx (P<0.001), GRx (P<0.01), and TAC (P<0.01) levels.
4. Discussion and Conclusion 
Under the NOR test, a decrease in the DI was observed in ASD rats, indicating learning and memory impairment. Treatment by SE and SNP increased the DI, where SNP had a higher effect on VAP-induced learning and memory impairment. The results of this study revealed that SNP was more effective than SE. The effect of SNP was significantly higher than that of SE on cognitive function, enzymatic activities, and TAC. Natural products of sumac make treatment of neurodegenerative diseases difficult due to low bioavailability and absorption, caused by poor fat solubility and stability and rapid degradation after intestinal absorption. SNP has greater permeability into neurons in the brain than SE. In agreement with our findings, Nazari et al. reported that nano-phytosome of garlic essential oil increased bioavailability and stability [11]. Khalaj et al. [12] reported that the effect of treatment by nano- hesperetin was higher compared to hesperetin on antioxidant activities and behavioral disorders in ASD rats. Molaveisi et al. [13] reported that oral bioavailability was improved by echinacea extract phytosome developed for oral consumption. In conclusion, SNP has promising effects on neuropathological disorders such as ASD.

Ethical Considerations
Compliance with ethical guidelines
All procedures were according to ethical guidelines for the use of animals in research of the University of Mazandaran (Code: IR.UMZ.REC.1397.021).

Funding
This study was supported by the Cognitive Science and Technologies Council of Vice Presidency for Science and Technology (Grant Number: 0786).

Authors' contributions
Conceptualization, supervision, editing & review: Akbar Hajizadeh Moghaddam; Data collection: Haniyeh Abbasalipour; Data analysis: Mojtaba Ranjbar and Sedigheh Khanjani Jelodar.

Conflicts of interest
The authors declare no conflict of interest.

Acknowledgements
The authors would like to thank the Deputy for Research of the University of Mazandaran for their cooperation.


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