Signal-level determinants of cognitive decline with PPIs versus H2RAs: 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.