AD is a degenerative neurological disease that impairs memory and cognitive function in older people [30]. Exposure to pesticides, heavy metals, and chronic medication use also contribute to the development of AD in the modern world. PPIs are a group of medications used to treat conditions related to stomach acid, such as gastroesophageal reflux disease and peptic ulcer disease. They work primarily by acting as irreversible inhibitors of the H+/K+-ATPase pump to reduce stomach acid production [31]. PPIs are among the most commonly prescribed medications in recent years due to their high level of safety and demand. According to the National Health and Nutrition Examination Survey, from 1999 to 2012, the percentage of adults aged 40–60 who received a prescription for PPIs almost doubled from 4.9–8.3% in the United States [32, 33]. Overall, long-term use of PPIs (lansoprazole) has increased, leading to potential adverse effects such as nutritional deficiencies (vitamin B12, iron and magnesium), osteoporotic fracture, renal damage, infection by Clostridium difficile, rhabdomyolysis, thrombocytopenia and anaemia. Because of these side effects, their safety and relevance in cognitive function (including the risk of developing AD, dementia) have recently been questioned. Several studies have found a link between PPIs and an increased risk of developing dementia and AD in the elderly [34]. However, other study has not shown that PPIs were associated with a greater risk of dementia. Thus, the present study was conducted to establish lansoprazole-induced neurobiological alteration as an animal model of AD in rats. Our findings showed that rats received lansoprazole for 28 days had behavioural changes, increased pro-inflammatory cytokines, have dysbalanced neurotransmitters, and produced biochemical alterations in the brain. In rats, chronic lansoprazole exposure induced neurobiological alteration as measured by MWM, and actophotometer. Lansoprazole administration substantially lost spatial memory in the MWM test, as seen by increased time to reach the platform, latency time, and reduced locomotor activity. According to existing evidence, oxidative stress and neuroinflammation both contribute to the etiology of neurodegenerative disorders. Antioxidants may play a potential role in AD treatment via suppressing oxidative stress [35]. Lansoprazole-induced cognitive impairment can be correlated to an elevated the amount of reactive oxygen species (ROS) in rats due to deficient antioxidant enzymes and free radical levels. In the present study, Lansoprazole treatment groups reduced antioxidant enzymes such as SOD, GSH, and catalase in the brain's hippocampus regions. Furthermore, in these areas, lansoprazole-exposed rats increased LPO and nitrite levels. In addition, we found that lansoprazole at a high dosage (30 mg/kg, p.o.) significantly increased oxidative stress and depleted anti-oxidant enzymes compared to a low dose (15 mg/kg p.o.).
PPI pretreatment might sensitize tumor cell lines to the effects of chemotherapeutic medicines and directly cause tumor cell death by blocking stomach H+/K+-ATPases, PPIs have been demonstrated to trigger apoptosis preferentially in gastric cancer cells. It has been found to promote apoptosis in gastric cancer cells, specifically via blocking stomach H+/K+-ATPases [36]. PPIs may trigger apoptosis in human B-cell malignancies by significantly altering the control of pH gradients, including ROS generation. PPIs may suppress H+/K+ ATPase expression, reverse the transmembrane pH gradient, and sensitize SGC7901 cells to anti-tumor drugs by reversing the transmembrane pH gradient [37]. Cytokines promote neuroinflammation and a variety of inflammatory responses associated with dementia [38]. Lansoprazole administration significantly elevated the levels of various pro-inflammatory mediators in the hippocampus, including TNF-α, IL-6, and IL-1β, and activated inflammatory cascades, leading to decreased neuronal function Fig. 1 (a). The ACh is a neurotransmitter found in the basal ganglia, cortex, and basal forebrain. Some neuropathological markers of AD, including the cholinergic deficit, extracellular deposition of amyloid-β (Aβ plague), development of intraneuronal neurofibrillary tangles (NTFs), glutamate excitotoxicity, and neuroinflammation, have profoundly affected recent therapeutic approaches of AD. Reduced ACh concentrations in AD cause a gradual and substantial decline in cognitive and behavioral function [39].
According to published evidence, the balance of GABA to glutamate affects neuronal signaling pathways, although excessive glutamate activation may affect normal nervous system function [39]. In the present research work, rats given lansoprazole had cholinergic neuron damage, decreased GABA levels, and elevated glutamate levels in the hippocampus in a dose-dependent manner. PPIs prevent acidic hydrogen ions from being transported from the cells that make up the mucosa. When the pumps are not operating, the amount of acid produced decreases, as does the corrosive damage to tissue. In earlier research, people who use PPIs have been linked to an increased risk of dementia [40], but the exact mechanism remains unclear until now.
The blood-brain barrier (BBB) is partially constructed by vascular endothelial cells, which make up the brain's capillaries and microvessels. This barrier maintains homeostasis within the brain microenvironment and protects the brain from changes in the peripheral environment [41]. The most accurate method for determining the BBB's functional integrity is to inject a dye into the bloodstream and measure its penetration into the brain [42]. Rat brain tissues were taken two hours after EB dye injection and subjected to photo-spectrometric analysis to determine the EB dye concentration. The present investigation observed an increase in the concentration of EB extravasation in the lansoprazole group due to BBB cell membrane disruption in the rat brain. The findings indicated that lansoprazole might alter the permeability and integrity of the BBB, hence causing a harmful effect on the central nervous system and causing neuronal death.
Additionally, lansoprazole interferes with the phagocytosis of Aβ peptides by downregulating the detecting membrane receptor through the NF-κB pathway, resulting in the buildup of Aβ 1-42 peptides in the brain. In the current study, rats treated with lansoprazole increased the phosphorylation of tau protein, and Aβ activates by activating tau-targeting kinases. Lansoprazole affects the phagocytosis of Aβ peptides by downregulating the membrane receptor through the NF-κB pathway, which leads to a buildup of Aβ 1-42 peptide in the brain. It has been reported that lansoprazole has been shown increased Aβ37, Aβ40, and Aβ42 production while decreasing Aβ38 levels. In wild-type and AD transgenic mice, acute lansoprazole therapy resulted in increased Aβ40 levels in the brain, suggesting that lansoprazole may worsen Aβ production in vivo [8]. Similarly, our investigation found that lansoprazole treatment raised the amount of Aβ in the hippocampus of rats. Our study discovered that lansoprazole might increase the synthesis of Aβ in animals. Similarly, in our study, rats treated with lansoprazole increased the level of Aβ in the hippocampus. Our research found that lansoprazole can augment Aβ production in rats.