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. 2024;24(20):1816-1828.
doi: 10.2174/0115680266320808240709061445.

The General Neurocognitive Decline in Patients with Methamphetamine Use and Transient Methamphetamine-induced Psychosis is Primarily Determined by Oxidative and AGE-RAGE Stress

Michael Maes  1   2   3   4   5   6   7   8   9 , Mazin Fadhil Altufaili  10 , Amer Fadhil Alhaideri  11 , Shatha Rouf Moustafa  12 , Kristina Stoyanova  6   7   9 , Mengqi Niu  1   2 , Bo Zhou  1   2 , Jing Li  1   2 , Hussein Kadhem Al-Hakeim  10
Affiliations

The General Neurocognitive Decline in Patients with Methamphetamine Use and Transient Methamphetamine-induced Psychosis is Primarily Determined by Oxidative and AGE-RAGE Stress

Michael Maes et al. Curr Top Med Chem. 2024.

Abstract

Background: Chronic Methamphetamine (MA) usage is linked to oxidative and AGE (advanced glycation end products) - RAGE (receptors for AGEs) stress, changes in magnesium, calcium, and copper, increased psychotic symptoms, and neurocognitive deficits. Nevertheless, it is still unclear whether these biological pathways mediate the latter impairments.

Objective: This study aimed to investigate the relationships between neurocognition, the aforementioned biomarkers, and psychotic symptoms.

Methods: We recruited 67 participants, namely 40 patients diagnosed with MA-substance use and 27 healthy controls, and assessed the Brief Assessment of Cognition in Schizophrenia (BACS), symptoms of psychosis, excitation, and formal thought disorders, oxidative toxicity (computed as the sum of myeloperoxidase (MPO), oxidized high-density lipoprotein (HDL), oxidized low-DL, and malondialdehyde), antioxidant defenses (catalase, glutathione peroxidase, total antioxidant capacity, zinc, and HDL), and increased AGEs and RAGEs.

Results: We were able to extract one validated latent vector from the Mini-Mental State Examination score and the BACS test results (including executive functions, verbal fluency, and attention), labeled general cognitive decline (G-CoDe). We found that 76.1% of the variance in the G-CoDe was explained by increased oxidative toxicity, lowered antioxidant defenses, number of psychotic episodes, and MA dose. In patients with MA use, MPO was significantly associated with the GCoDe.

Conclusion: The use of MA induced mild cognitive impairments through MA-induced activation of detrimental outcome pathways, including oxidative and AGE-RAGE stress, and suppression of protective antioxidant pathways. Increased MPO, oxidative, and AGE-RAGE stress are new drug targets to prevent neurocognitive deficits and psychosis due to MA use.

Keywords: Antioxidants; Biomarkers; Neurocognition.; Oxidative and nitrosative stress; Pathophysiology; Schizophrenia.

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References

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