Chronic alcohol consumption is well-documented to cause widespread structural and functional brain impairments (Oscar-Berman and Marinkovic 2003; Zahr et al. 2011; Nunes et al. 2019; Rao and Topiwala 2020). Alcohol is a potent amnestic agent (White and Swartzwelder 2004) that particularly disrupts hippocampal function, thereby significantly impairing memory consolidation and retrieval processes (Aggleton 2014; Jauhar et al. 2014; Aggleton and Morris 2018). These disruptions frequently manifest as memory deficits, which are hallmark features of alcohol-related brain damage, especially during critical developmental windows such as adolescence (Hanson et al. 2011; Jacobus and Tapert 2013). In addition to its effects, alcohol inhibits the proliferation and survival of neural progenitor cells in the hippocampus (Nixon and Crews 2002), thereby impairing hippocampal neurogenesis and promoting neurodegeneration (He et al. 2005; Zeigler et al. 2005; Crews et al. 2006; Mira et al. 2020; Doremus-Fitzwater and Deak 2021; Anand et al. 2023). These neurobiological changes underlie many of the cognitive impairments associated with alcohol exposure. Furthermore, neuroimaging studies have revealed that adolescents with a history of alcohol use exhibit significantly reduced hippocampal and prefrontal cortex volumes compared to non-drinking peers (De Bellis et al. 2000; Bellis et al. 2005; Nagel et al. 2005; Oscar-Berman and Marinković 2007), highlighting the vulnerability of the developing brain to alcohol-induced damage.

Alcohol-induced neurodegeneration is closely linked to the upregulation of oxidative stress, a condition characterised by an excessive accumulation of reactive oxygen species (ROS) within cells. These highly reactive molecules cause significant damage to critical biomolecules such as lipids, proteins, and nucleic acids, ultimately impairing cellular integrity and function (Betteridge 2000). Oxidative stress has been implicated in the pathogenesis of various neurodegenerative diseases, including epilepsy, Huntington’s disease, and Parkinson’s disease (Aguiar et al. 2012; Kim et al. 2015). Among brain regions, the hippocampus is particularly vulnerable to alcohol-induced oxidative damage (Enache et al. 2008; Fowler et al. 2014; Rajput et al. 2017; Tsermpini et al. 2022). Alcohol exposure triggers a cascade of detrimental events within the hippocampus, including mitochondrial dysfunction, impaired neuronal signalling, neuronal apoptosis, and suppressed neurogenesis (Hovatta et al. 2010; Brocardo et al. 2011). Compounding these effects, alcohol reduces the activity of key endogenous antioxidant enzymes, such as SOD and GSH-Px, which are essential for cellular detoxification and the maintenance of redox homeostasis (Huang et al. 2009; Contreras-Zentella et al. 2022; Shen et al. 2022). Furthermore, excessive oxidative stress plays a pivotal role in the initiation of apoptosis following exposure to xenobiotic agents such as alcohol (Bhattacharyya et al. 2014; Jelinek et al. 2021), thereby exacerbating neuronal loss and contributing to long-term cognitive and structural deficits.

In the present study, MDA levels across the experimental groups were similar in both sexes. These findings contradict studies that consistently show that alcohol exposure leads to significant increases in MDA levels in the hippocampus of rodents, which is indicative of lipid peroxidation and oxidative stress. Smith et al. (2005), Rajput et al. (2017) and Pamplona-Santos et al. (2019) all reported similar findings, emphasising that chronic alcohol consumption causes oxidative damage in the hippocampus. Furthermore, Zeigler et al. (2005), Tiwari and Chopra (2013) and Pant et al. (2017) highlight that alcohol-induced oxidative stress in the hippocampus can lead to neuronal injury, which may contribute to cognitive deficits. Simvastatin also significantly reduces MDA levels in the hippocampus of rodents, indicating its potential as an antioxidant agent. Eger et al. 2016a, b; Zhang et al. (2016); Jafari et al. (2021) also showed that Simvastatin mitigates oxidative stress in the hippocampus, reducing lipid peroxidation as reflected by lower MDA levels. Cimino et al. (2005) and Lietzau et al. (2023) also reported the neuroprotective benefits of Simvastatin in models of neurodegeneration and ischemia.

Alcohol has been shown to impair hippocampal antioxidant defences, primarily through the reduction of glutathione peroxidase (GSH-Px) activity, therefore promoting oxidative stress and increasing the risk of neurotoxicity (Herrera et al. 2003; Almansa et al. 2013; Tsermpini et al. 2022). Interestingly, conflicting findings have emerged from clinical studies. Wu et al. (2020) reported elevated serum GSH-Px levels in individuals with alcohol use disorder (AUD) compared to healthy controls, a trend similarly observed by Guemouri et al. (1993) and Chen et al. (2011). These discrepancies may reflect compensatory upregulation in peripheral tissues or differences in the chronicity and severity of alcohol exposure, highlighting the complexity of systemic antioxidant responses. In contrast, Simvastatin has been shown to upregulate GSH-Px activity and alleviate oxidative stress (Eger et al. 2016a, b; Zinellu and Mangoni 2021; Mansouri et al. 2022). Its antioxidant and anti-inflammatory properties have been documented across several pathological models, including traumatic brain injury (Lim et al. 2017), senile dementia (Liu et al. 2018), sepsis (Catalão et al. 2017), and alcohol-induced neurotoxicity (Jafari et al. 2021). In these contexts, Simvastatin reduced oxidative damage and preserved neuronal integrity, reinforcing its potential as a neuroprotective agent capable of safeguarding hippocampal function, which is critical for cognitive processes such as learning and memory.

In the present study, GSH-Px activity was highest in the alcohol group in both sexes. A possible explanation for these observations is a compensatory up-regulation of antioxidant enzymes in response to alcohol-induced oxidative stress. However, the elevated alcohol-induced oxidative stress was mitigated by Simvastatin, evident by a significant reduction in GSH-Px activity in the SIM, ALC + SIM5, and ALC + SIM15 groups compared to the alcohol group, indicating its ability to counteract oxidative stress. These findings suggest that Simvastatin mitigated alcohol-induced oxidative stress, as evidenced by a reduction in GSH-Px activity, thereby reinforcing its antioxidant capacity even under conditions of elevated ROS production. In support of the present findings, ROS are known to upregulate antioxidant enzymes such as GSH-Px as part of the cellular adaptive defence mechanism. This response is primarily mediated by redox-sensitive transcription factors like Nrf2, which enhance the expression of antioxidant genes in response to oxidative stress (Ma 2013; Pizzino et al. 2017; Zhang et al. 2017a, b). Conversely, under conditions of excessive or prolonged oxidative stress, ROS can cause oxidative damage to these enzymes, thereby impairing their function (Pizzino et al. 2017).

SOD is another key antioxidant enzyme that helps maintain redox balance and detoxifies harmful molecules in living organisms. It plays a crucial role as the first line of defence against reactive nitrogen species (RNS), ROS, and other dangerous molecules by catalysing the conversion of O2− into molecular oxygen (O2) and H2O2 (Younus 2018; Chidambaram et al. 2024). Studies show that chronic alcohol use leads to a decrease in SOD activity, disrupting the brain’s antioxidant defence system which may contribute to neurological dysfunction and cognitive deficits (Marklund et al. 1983; Huang et al. 2009; Yang et al. 2022; Kado et al. 2024). On the otherhand, Simvastatin boosts SOD activity thereby increasing its antioxidant effect to counteract oxidative damage in the hippocampus (Eger et al. 2016a, b; Catalão et al. 2017; Zhang et al. 2017a, b; Liu et al. 2018). In an experimental model of sepsis (Catalão et al. 2017) and alcohol-induced neurotoxicity model (Jafari et al. 2021), Simvastatin has been shown to protect the hippocampus from oxidative damage by increasing SOD activity, further confirming its neuroprotective properties. Additionally, in an Alzheimer’s disease model (Adeli et al. 2017), Simvastatin prevented cognitive decline by increasing SOD activity.

In the present study, the effect of chronic alcohol on SOD activity in the mice was found to be non-significant in both sexes, which aligns with some studies that suggest alcohol may not always affect SOD activity in specific tissues or under certain conditions. For instance, Enache et al. (2008) reported no significant changes in SOD activity in rat brains following chronic alcohol exposure in a prenatal restraint stress rat model, suggesting that alcohol-induced oxidative stress may not always result in direct alterations to SOD levels in all tissues. The lack of change in SOD activity may be attributed to several factors, including tissue-specific antioxidant responses, the duration and dosage of alcohol exposure, or adaptive mechanisms that compensate for alcohol-induced oxidative stress.

The differences between the present and previous studies highlight the complex, multifactorial nature of oxidative damage and antioxidant regulation (Singh and Singh 2008). It is possible that other enzymes or mechanisms, such as GSH-Px, were more prominently upregulated to counteract the ROS generated during alcohol metabolism. This may reflect a shift in the antioxidant defence system away from SOD, suggesting that alternative enzymatic pathways could be more responsive to alcohol-induced oxidative stress in rodent models. As highlighted by Ruiter-Lopez et al. (2025), alcohol-induced oxidative stress does not uniformly affect all antioxidant systems in all tissues, which suggests that future studies should consider a more nuanced approach, taking into account the tissue-specific antioxidant responses and mechanisms that may be activated in the presence of alcohol. Furthermore, other factors, such as the strain of rodents used, age, and gender, may influence the antioxidant defence system, complicating the interpretation of results.

Neurogenesis, the process of generating new neurons from neural stem cells, continues from adolescence into adulthood, primarily in the subventricular zone (SVZ) of the lateral ventricles and the SGZ of the DG in the hippocampus (Crews et al. 2006; Gil-Perotín et al. 2009; Lazarov and Hollands 2016). In the SGZ, neural progenitor cells proliferate, differentiate into glial cells or neurons, and migrate into the GCL, where they integrate into hippocampal circuits involved in learning, memory (Shors et al. 2001), and mood regulation (Malberg et al. 2000). Neurogenesis is particularly active during adolescence, occurring at rates up to four times higher than in adulthood, contributing to increased granule cell density and hippocampal volume (Sousa et al. 1998; Hueston et al. 2017; Boldrini et al. 2018). Various intrinsic factors (e.g., neurotrophic factors, neurotransmitters) and extrinsic factors (e.g., stress, alcohol, and environmental stimuli) regulate hippocampal neurogenesis (Åberg et al. 2005; Cameron and Glover 2015; Opendak et al. 2016).

Alcohol exposure, particularly during adolescence, induces neurotoxicity, leading to cognitive impairments and altered hippocampal function (White and Swartzwelder 2004; Zeigler et al. 2005; Peeters et al. 2014; Risher et al. 2015). In this study, neurogenic patterns remained consistent across experimental groups, with no significant morphological changes observed following alcohol exposure or Simvastatin treatment, aligning with previous findings on adolescent hippocampal neurogenesis (Crews et al. 2006; Broadwater et al. 2014; Robin et al. 2014). However, proliferative cell distribution (PcNA- and DCX-positive cells) was significantly reduced in the alcohol-exposed group compared to others, confirming the inhibitory effects of alcohol on neurogenesis.

These findings align with previous studies reporting alcohol-indu