Ranitidine Alleviates Anxiety-like Behaviors and Improves the Density of Pyramidal Neurons upon Deactivation of Microglia in the CA3 Region of the Hippocampus in a Cysteamine HCl-Induced Mouse Model of Gastrointestinal Disorder

Abstract

Elevated levels of histamine cause over-secretion of gastric hydrochloric acid (HCl), leading to gastrointestinal (GI) disorders and anxiety. Ranitidine is an antihistamine drug widely used in the management of GI disorders, as it works by blocking the histamine−2 receptors in parietal cells, thereby reducing the production of HCl in the stomach. While some reports indicate the neuroprotective effects of ranitidine, its role against GI disorder-related anxiety remains unclear. Therefore, we investigated the effect of ranitidine against anxiety-related behaviors in association with changes in neuronal density in the hippocampal cornu ammonis (CA)–3 region of cysteamine hydrochloride-induced mouse model of GI disorder. Results obtained from the open field test (OFT), light and dark box test (LDBT), and elevated plus maze (EPM) test revealed that ranitidine treatment reduces anxiety-like behaviors in experimental animals. Nissl staining and immunohistochemical assessment of ionized calcium-binding adapter molecule (Iba)-1 positive microglia in cryosectioned brains indicated enhanced density of pyramidal neurons and reduced activation of microglia in the hippocampal CA–3 region of brains of ranitidine-treated experimental mice. Therefore, this study suggests that ranitidine mediates anxiolytic effects, which can be translated to establish a pharmacological regime to ameliorate anxiety-related symptoms in humans.

Cysteamine HCl Administration Impedes Motor and Olfactory Functions, Accompanied by a Reduced Number of Dopaminergic Neurons, in Experimental Mice: A Preclinical Mimetic Relevant to Parkinson’s Disease

“…Moreover, somatostatin pretreatment in experimental rat models mimicking PD has been reported to show resistance against lipopolysaccharide-induced neurodegeneration in the SN by preventing the activation of microglia and the accumulation of reactive oxygen species [33]. In a recent finding, we demonstrated that the administration of Cys-HCl induced an anxiety-like phenotype in the experimental animals in correlation with the reduced neuronal density and increased activation of microglia cells in the hippocampus [8,18]. While, in the intact brain, somatostatin plays a key role in olfaction and mood, affective disorders and olfactory dysfunctions have been established as non-motor clinical symptoms of many neurodegenerative disorders, including PD [30,34,35].…”

“…PD has been linked to the inhibition of mitochondrial monoamine oxidase, which might be highly relevant in the context of the reduced levels of dopaminergic neurons in the brains of Cys-HCl-treated mice [44,45]. The Cys-HCl administration-induced reduction in antioxidants in experimental brains has become increasingly evident [18]. The anticancer effect of Cys-HCl has been reported to be associated with mitochondrial degeneration linked to the accumulation of iron, and this event activates peroxidase-positive autophagosomes, ultimately leading to cell death [46,47].…”

“…The mice (N = 12) were divided into two experimental groups: the control group (N = 6), which received intraperitoneal injections of sterile water, and the Cys-HCl group (N = 6), which received intraperitoneal injections of 60 milligrams (mg)/kilogram (kg) of body weight (BW) of Cys-HCl for three alternative days for a total of three doses. The dose and concentration of Cys-HCl, as well as the choice of vehicle, were as described earlier [18]. After 14 days, the animals were exposed to the respective behavioral apparatuses and arenas for acclimatization and basic training prior to each experiment.…”

Cysteamine HCl Administration Impedes Motor and Olfactory Functions Accompanied by Reduced Dopaminergic Neurons in Experimental Mice: A Preclinical Mimetics Relevance to Parkinson’s Disease

“…Moreover, pretreatment of somatostatin in experimental rat models mimicking PD has been reported to show resistance against lipopolysaccharide-induced neurodegeneration in SN by preventing the activation of microglia and accumulation of reactive oxygen species [26]. In a recent findings, we have demonstrated that administration of cysteamine HCl induced anxiety-like phenotype in the experimental animals in correlation with reduced neuronal density and increased activation of microglia cells in the hippocampus [8,27]. While in the intact brain, somatostatin plays a key role in olfaction and mood, affective disorders and olfactory dysfunctions have been established as nonmotor clinical symptoms of many neurodegenerative disorders including PD [23,28,29].…”

“…PD has been linked to the inhibition of mitochondrial monoamine oxidase, which might be highly relevant in the context of reduced levels of dopaminergic neurons in the brain of cysteamine HCl-treated mice [38,39]. Meantime, cysteamine administrationinduced reduction of antioxidants in the experimental brains has become incorrectly evident [27]. The anticancer effect of cysteamine has been reported to be associated with mitochondrial degeneration linked to the accumulation of iron and this event activates peroxidase-positive autophagosomes, ultimately leading to cell death [40,41].…”