Signal‐Level Determinants of Cognitive Decline With PPIs versus H ₂ RAs: Transportome (CBLIF/TCN2) and CHRNA7 Nodes

Emerging evidence suggests that chronic use of gastric acid-suppressing medications may contribute to neurocognitive decline, yet the underlying mechanisms remain poorly defined. Proton pump inhibitors like omeprazole and histamine-2 receptor antagonists such as ranitidine are widely prescribed for gastrointestinal disorders, but their long-term impact on brain function. Forty-eight male Wistar rats were assigned to six groups receiving either control diet, B₁₂ alone, omeprazole, ranitidine, or co-treatment with B₁₂ for 90 days. Behavioral and cognitive assessments revealed early deficits in the drug-only-treated groups (omeprazole and ranitidine). Notably, B₁₂ ameliorated omeprazole-induced impairments but failed to reverse ranitidine-associated deficits, suggesting divergent neurotoxic pathways. Biochemical profiling included serum B₁₂, homocysteine, cortisol, glucose, insulin, liver enzymes, and neurotransmitter. To complement these in vivo findings, an in silico approach was employed to explore molecular interactions of omeprazole and ranitidine with proteins critical for vitamin B₁₂ transport (CBLIF and TCN2) and cholinergic neurotransmission (CHRNA7). Together, these in vivo and in silico results suggest that omeprazole-induced cognitive decline may involve B₁₂ depletion and other mechanisms, whereas ranitidine likely acts via alternative pathways. This study provides novel mechanistic insights into differential cognitive risks associated with chronic acid-suppressing therapy, with implications for long-term management in populations vulnerable to neurodegeneration.