Novel insights on the probable mechanism associated with histamine oral model‐inducing neuropathological and behavioral toxicity in rats

Abstract Histamine (HIS) is an important chemical mediator that causes vasodilation and contributes to anaphylactic reactions. Recently, HIS is an understudied neurotransmitter in the central nervous system, and its potential role in neuroinflammation and neurodegeneration is a critical area of research. So, the study's goal is to investigate the consequences of repeated oral intake of HIS on the rat's brain and explore the mechanistic way of its neurotoxicity. Thirty male rats were divided into three groups ( n = 10). The following treatments were administered orally to all rats every day for 14 days. Group (1) was given distilled water, whereas groups (2 & 3) were given HIS at dosage levels 250 and 500 mg/kg body weight (BWT), respectively. Brain tissue samples were collected at 7‐ and 14‐days from the beginning of the experiment. Our results revealed that continuous oral administration of HIS at both doses for 14 days significantly reduced the BWT and induced severe neurobehavioral changes, including depression, dullness, lethargy, tremors, abnormal walking, and loss of spatial learning and memory in rats. In all HIS receiving groups, HPLC data showed a considerable raise in the HIS contents of the brain. Additionally, the daily consumption of HIS causes oxidative stress that is dose‐ and time‐dependent which is characterized by elevation of malondialdehyde levels along with reduction of catalase activity and reduced glutathione levels. The neuropathological lesions were commonly observed in the cerebrum, striatum, and cerebellum and confirmed by the immunohistochemistry staining that demonstrating moderate to strong caspase‐3 and inducible nitric oxide synthase expressions in all HIS receiving groups, mainly those receiving 500 mg/kg HIS. NF‐κB, TNF‐α, and IL‐1β gene levels were also upregulated at 7‐ and 14‐days in all HIS groups, particularly in those getting 500 mg/kg. We concluded that ROS‐induced apoptosis and inflammation was the essential mechanism involved in HIS‐mediated neurobehavioral toxicity and histopathology.