Effects of Quercetin against fluoride-induced neurotoxicity in the medial prefrontal cortex of rats: A stereological, histochemical and behavioral study.

Fluoride is widely found in groundwater, soil, toothpaste and food (Ullah et al., 2017). A low level of fluoride (<5 ppm) can support the mineralization of bones and teeth (Adkins and Brunst, 2021). In countries with very low levels of fluoride in the groundwater, fluorosilicic acid, sodium fluorosilicate and sodium fluoride (NaF) are usually added to the water (Fluoridation process) to reduce tooth decay (Adkins and Brunst, 2021). The optional recommended level of fluoride has been suggested to be 1 ppm (Duffin et al., 2022). In some regions of the world, excessive amount of fluoride in groundwater or fluoridated water leads to health problems such as dental and skeletal fluorosis (El-Megharbel et al., 2021). There are some controversies about the effects of fluoride on human health. A low dose of fluoride can prevent dental caries and strengthen bones while a high dose of fluoride can cause a variety of adverse effects (Adkins and Brunst, 2021).Previous animal studies have indicated that exposure to 100 and 200 ppm of fluoride through drinking water for 21 days resulted in the deposition of fluoride in various parts of the brain and caused oxidative damage in different parts of the brain by increasing lipid peroxidation and decreasing antioxidant enzymes (Basha et al., 2011a).

It has been recently reported that fluoride exposure during brain development can lead to lower intelligence in childhood (Miranda et al., 2021). To evaluate the adverse effects of fluoride in the central nervous system (CNS), NaF is usually used to induce animal models of fluoride toxicities (Adkins and Brunst, 2021). Exposure to NaF during critical periods of CNS development leads to depression, anxiousness and learning defects after birth (Kinawy, 2019). In adult mice, excessive fluoride consumption was associated with impaired memory and anxiety like behaviors (Bartos et al., 2022). NaF exposure causes oxidative stress in different soft tissues such as the kidney, liver and brain (Ma et al., 2022). NaF as a neurotoxic agent can cause mitochondrial dysfunction, ROS overproduction, lipid peroxidation and apoptosis (Lopes et al., 2020). Besides of oxidative stress, neuroinflammation was also introduced as a possible harmful consequence of NaF exposure in the CNS (Reddy et al., 2021). Excessive fluoride intake in rats led to neurotransmitter irregularities, disruption of myelin sheaths and enlarged axons (Niu et al., 2018b). Oxidative stress was introduced as the most crucial reason for neurodegenerative disorders and cerebrovascular disease (Agustina et al., 2019).

Quercetin (3,3_,4_,5,7-pentahydroxyflavone) is a common flavonoid that belongs to the Flavonol subfamily (Pandey and Rizvi, 2009; Portillo, 2011). The free and glycosylated forms of Quercetin can be found in different plants such as vegetables and fruits (Pandey and Rizvi, 2009; Portillo, 2011). The antioxidant potency of Quercetin is the most accepted effect of Quercetin against different disorders (Suganthy et al., 2016). The beneficial effects of Quercetin against CNS disorders are related to its anti-inflammatory, anti-cancer and antioxidant features (Suganthy et al., 2016). Also, Quercetin can enhance neurogenesis and neuronal survival which consequently leads to improved memory and cognitive performance (Javanbakht et al., 2023; Karimipour et al., 2019). It has been widely demonstrated that brain is highly vulnerable to oxidative conditions and the overproduction of reactive oxygen species (ROS) (Vinokurov et al., 2021). Therefore, oxidative stress caused by any possible reasons can lead to cell degeneration (neurons and glial cells) and destructive processes in the brain. Recently, a vast amount of preclinical data has indicated that Quercetin is a promising choice for protecting CNS against oxidative stress damage (Dajas, 2012). Beneficial effects of Quercetin have been reported in different animal models of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, spinal cord injury, Huntington’s disease and depression (El-Horany et al., 2016; Fan et al., 2019; Jain and Gangshettiwar, 2014; Sabogal-Guáqueta et al., 2015; Samad et al., 2018). Quercetin can easily diffuse across the blood brain barrier (BBB) and distribute in different parts of the brain (Dajas et al., 2015).

Medial prefrontal cortex (mPFC) is an important cortical region in the rodent brain which controls cognition and emotional processes such as memory, aggression, pain, depression and anxiety (Schneider and Koch, 2005). The mPFC has connections with several cortical, limbic, and thalamic structures and there is also functional interaction between the PFC and the striatum (Schneider and Koch, 2005). Based on anatomical and physiological aspects, the rodent mPFC is similar to the anterior cingulate cortex and dorsolateral prefrontal cortex of primates (Xu et al., 2019). Dysfunction of the mPFC has been reported in different neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and autism spectrum disorders (ASD) (Xu et al., 2019). In recent years, the mPFC has attracted the focus of considerable scientific investigations, because prefrontal cortex dysfunction underlies most of the cognitive and behavioral disturbances associated with major neuropsychiatric disorders (Bast et al., 2017).

To the best of the author’s knowledge, there is no published report about the protective property of Quercetin against NaF-induced toxicity in the mPFC of rats. In this study, we investigate the mitigating role of Quercetin against NaF-induced neurotoxicity in the mPFC of rats via oxidative, behavioral, quantitative real-time PCR, and stereological analysis.