Substance use disorder (SUD), identified as a risk factor for stroke, and poses an escalating global risk particularly among young adults. Prevention strategies are considered primary interventions (Schulte & Hser, 2014). In Egypt, the proliferation of substance abuse constitutes a significant public health challenge, with tramadol noted as one of the substances most frequently misused [14] (Fig. 9).

Fig. 9

MRI and MRA show bilateral parietal lobe infarctions in the distribution of the MCA. Diffusion_weighted axial image: A of the brain MRI showed acute infarcts in both parietal lobes, B MRA showed vasospasm of the right internal carotid artery and complete occlusion of the left internal carotid artery

Numerous genes have been implicated in the pathogenesis of stroke, yet only a select few have been definitively proven to affect susceptibility. Furthermore, considerable research has been directed towards understanding the role of microRNAs (miRNAs) in stroke, given their expression levels are correlated with the prognosis of this ailment [15].

The objective of this study was to clarify the potential significance of genetic factors (CYP4A11 and CYP2E1) in the diagnosis of stroke and to assess the association between miRNA (miR-214-3p and miR-27b) expression and stroke occurrence.

According to our results, tramadol was the most commonly abused drug. This finding was also reported by Rizk and colleagues [16], who mentioned that tramadol addiction was observed in 53.7% of their patients.

The current investigation reveals that lesions may manifest across all cerebral regions, corroborating the observations made by Tsatsakis and colleagues [1], who noted that strokes attributable to drug abuse may arise in any area of the brain. Conversely, Middlekauff and colleagues [17] identified that cannabis-induced multifocal intracranial stenosis predominantly affects the posterior circulation.

There was a statistically significant difference between both groups regarding CYP4A11 and hsa-miR-214-3p expression. CYP4A11 expression was downregulated with a highly significant difference from the control group, showing a diagnostic value with an area under the curve (AUC) of 1, 98.9% sensitivity, and 90.9% specificity. This finding agrees with Solodilova and colleagues [18], who mentioned that CYP4A11 could be a novel genetic marker of susceptibility to coronary artery disease (CAD). Sirotina and colleagues [6] also mentioned that the polymorphism rs9332978 of CYP4A11 could be a novel marker of genetic susceptibility to CAD, at least in Europeans.

MicroRNA-214-3p was downregulated with a highly significant difference from the control group, showing a diagnostic value with an AUC of 1, 97.7% sensitivity, and 100% specificity. This is consistent with Ping and colleagues [19], who mentioned that miR-214 inhibits neuronal apoptosis by negatively regulating Bax, consequently attenuating ischemic injury in MCAO mice. These findings may provide a potential therapeutic target for stroke treatment. Shen and colleagues [20] also showed that the injection of miR-214 agomir promoted the expression of SOD and relieved the apoptosis of brain cells. Wu and colleagues [21] reported analogous findings, indicating that the suppression of miR-214-3p negates the pronounced efficacy of Hypo-Exo’s (exosomes sourced from mesenchymal stem cells cultured in hypoxic conditions) in facilitating the recovery process of the ischemic brain.

CYP2E1 was upregulated with a highly significant difference from the control group, showing a diagnostic value with an AUC of 0.741, 90.8% sensitivity, and 55.2% specificity. Yu and colleagues [22] documented that the inhibition of Cytochrome P450 CYP2E1 mitigates damage from cerebral ischemia–reperfusion.

miR-27b was upregulated with a highly significant difference from the control group, showing a diagnostic value with an AUC of 1, 100% sensitivity, and 97.7% specificity. This finding is consistent with the results of Xu and colleagues [23], who determined that the inhibition of miR-27b could diminish neurological deficits by curtailing neuroinflammation and decreasing cellular mortality. This concurs with the observations by Wang and colleagues [11], who reported that inhibiting miR-27b enhances recuperation following ischemic stroke through modulation of AMPK activity.

Our result reveals that there was statistically non-significant correlation between size of infarction and CYP4A11, CYP2E1, hsa-miR-214-3p or miR-27b. This finding is consistent with the results of Ceren E and colleagues [24], who determined that miRNA-target gene networks based on inflammatory response, blood coagulation, platelet activation resulting in large artery stroke, small artery stroke, stroke due to undetermined cause and cardioembolic stroke.

Finally, our study had some limitations, the study focused on a specific set of molecular markers (CYP4A11, CYP2E1, miR-214-3p, and miR-27b). However, other CYP enzymes and miRNAs might also be involved in stroke pathogenesis in addicted patients. Future research should consider a broader range of molecular markers to provide a more comprehensive understanding. Future studies with larger, more diverse populations are needed to validate these results.

Given their potential as biomarkers, research should aim to validate the clinical utility of CYP4A11, CYP2E1, miR-214-3p, and miR-27b in predicting stroke risk among addicted patients. Large-scale cohort studies and clinical trials are needed to assess their predictive value and reliability. Investigating the possibility of targeting these pathways therapeutically could offer new avenues for stroke prevention and treatment in addicted individuals. Pharmacological modulation of CYP enzymes and miRNAs may reduce stroke incidence and improve outcomes in this high-risk group.

Limitations

We acknowledge that there are a number of limitations in this review including.

1.

ESUS work up including Holter ECG, TEE, collagen battery, autoimmune markers and thrombophilia protocol should be done and documented as the mean age of patients according to the study is 47 years.

2.

TCD studies should be done for all patients to assess the mean MCA/intracranial ICA diameter to document the vasospasm.