Consumption of saturated fat has been linked to oxidative stress, inflammation, reduced synaptic plasticity, and an increase in neuronal apoptosis, which can impair cognitive function. ROS can cause damage to cells and tissues, including the brain, leading to inflammation and cellular dysfunction. Treatments for obesity are scarce and in need of new options. Our results showed that ZO supplementation reverse cognitive impairment and oxidative parameters in the cortex after the establishment of obesity.
Obesity has been linked to cognitive decline and neurodegenerative diseases (Pasinetti and Eberstein 2008). Diets rich in fats and sugars not only compromise physiological health but also affect brain regions responsible for cognitive function (Pedroso et al. 2016). Studies on mice fed a high-fat diet have shown impaired recognition memory and spatial learning (Denver et al. 2018). In our findings, DIO over 4 months led to impaired recognition memory, which was reversed in obese animals supplemented with ZO for 35 days. Additionally, ginger supplementation reversed the detrimental effects of excessive oil consumption on spatial and recognition memory (Zarei et al. 2021). Ginger extract has also been found to enhance rats' ability to recognize new objects (Lim et al. 2014) and improve short-term memory function compared to long-term memory (Khaliq et al. 2017).
Neurons are vulnerable to oxidative damage, with obesity exacerbating neuronal fatty acid metabolism and ROS production, resulting in neuronal membrane peroxidation and apoptosis (Gancheva et al. 2017). In animals subjected to 8 weeks of DIO regimen, levels of malondialdehyde (MDA) in both peripheral and central tissues increased, exacerbating cerebral lipid peroxidation (Park t al. 2010). ZO extract enhanced antioxidant activity in the cortex of DIO mice by up regulating catalase activity, reducing DCFH production, and lowering protein carbonylation levels. Cognitive impairments stemming from neurodegenerative processes may stem from heightened oxidative stress (Sah et al. 2017). Ginger extract has been shown to diminish cerebral infarction and enhance cognitive function in rats, notably by bolstering antioxidant activity in the hippocampus and cortex (Wattanathorn et al. 2011). Additionally, ginger protects the brain from oxidative stress neurotoxicity induced by high doses of topiramate (Mabrouk et al. 2022), aligning with our study's findings, wherein ZO supplementation potentially improves recognition memory through enhanced antioxidant status and reduced oxidative stress.
The findings on anxiogenic effects resulting from dietary protocols vary; while a western diet high in saturated fatty acids is linked to anxiety and depressive states (Jang et al. 2019), DIO does not necessarily exhibit signs of anxiety (Hryhorczuk et al. 2017). In our study, DIO did not impact the evaluated anxiety parameters. The brain demonstrates considerable adaptive capacity, and the effects of DIO may be time-dependent (Muller et al. 2013); thus, after 5 months, these effects on parameters might no longer be present, or other changes associated with metabolic parameters may be necessary. A western diet inducing obesity resulted in fear memory impairment in rats, whereas 6-shogaol reversed these effects without affecting locomotor activity (Gabriel et al. 2020).
Ginger has demonstrated potential anxiolytic effects, such as increasing the time spent in the open arms of the elevated plus-maze (Hasenöhrl et al. 1996) or decreasing the duration of stay in the closed arms (Vishwakarma et al. 2002), suggesting the presence of anxiolytic compounds in this nutraceutical. Additionally, compounds found in ginger are known to inhibit monoamine oxidase (MAO), as evidenced by both in silico and in vivo experiments. MAO inhibition is involved in the metabolism of certain neurotransmitters and is a mechanism of action for some antidepressant drugs (Moorkoth et al. 2021)]. In our study, there were no differences between groups in the plus maze task. However, there was an increase in locomotor activity observed in the open field test in control animals supplemented with ZO, which may indicate the effects of this nutraceutical on metabolism and anxiety (Sestakova et al. 2013).
DIO is known to trigger a state of low-grade inflammation characterized by adipocyte hypertrophy (Guillemot-Legris and Muccioli 2017). This peripheral inflammation has the potential to induce neuroinflammation, impacting mood, anxiety, and cognitive functions (Baker et al. 2017). Neuroinflammation induced by DIO involves activated macrophages, elevated levels of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, and reduced levels and/or activity of neurotrophins such as BDNF and NGF (Cavaliere et al. 2019) with negative impact on cognition (Sahrma 2021). However, in our study, neither inflammation nor neurotrophin levels were affected by DIO or ZO supplementation. The effects of DIO on the brain may be rapid and transient (Kim et al. 2019), as could be the case with ginger supplementation (Pagano et al. 2021; Mohd and Makpol 2019). Therefore, longer-term consumption may induce adaptive changes without observable effects at the molecular level during experimental assessments.
In conclusion, our research underscores the profound impact of ZO supplementation on cognitive function in DIO mice, highlighting its potential as a therapeutic intervention for cognitive impairment. Our findings not only demonstrate a reversal of cognitive deficits but also reveal a notable enhancement in antioxidant status. While our study did not observe significant alterations in the levels of pro-inflammatory cytokines and neurotrophins following treatment, it is imperative to acknowledge the intricate molecular dynamics that may have been modulated, particularly during the initial phases of the experiment. Overall, ZO emerges as a promising and safe phytochemical adjunct for addressing cognitive impairment associated with obesity.