Depression is a highly prevalent mood disorder and one of the major health concerns in modern society. Moreover, it is characterized by a high prevalence of coexistence with many other diseases including metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. Currently used antidepressant drugs, which mostly target brain monoaminergic neurotransmission, have limited clinical efficacy. Although the etiology of depression has not been fully elucidated, current scientific data emphasize the role of neurotrophic factors deficiencies, disturbed homeostasis between the nervous system and the immune and endocrine systems, as well as disturbances in brain energy metabolism and dysfunctions in the gut-brain axis as important factors in the pathogenesis of this neuropsychiatric disorder. Therefore, therapeutic options that could work in a way other than classic antidepressants are being sought to increase the effectiveness of the treatment. Interestingly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), used in the treatment of T2DM and obesity, are known to show pro-cognitive and neuroprotective properties, and exert modulatory effects on immune, endocrine and metabolic processes in the central nervous system. This review article discusses the potential antidepressant effects of GLP-1RAs, especially in the context of their action on the processes related to neuroprotection, inflammation, stress response, energy metabolism, gut-brain crosstalk and the stability of the gut microbiota. Graphic abstract

Introduction: Recent data indicate that there is a link between depression and diabetes and that excess glucocorticoids may play an underlying role in the pathogenesis of both of these diseases. The aim of the present study was to determine whether there are any alterations in glucose, glycogen, glucose transporters, insulin, insulin receptors or corticosterone concentrations in the hippocampus and frontal cortex in a prenatal stress rat model of depression. Methods: Male rats whose mothers had been subjected to stress and control animals were subjected to the Porsolt test to verify the experimental model. Next, some of the rats were subjected to acute stress and/or were administered glucose. Glucose, glycogen, corticosterone, insulin, insulin receptor, phospho-insulin receptor and glucose transporter (GLUT1, GLUT3 and GLUT4) concentrations were assayed. Results: Prenatally stressed rats exhibited glucose and glycogen concentrations in both investigated brain structures that exceeded those of the control animals. Prenatal stress also increased the levels of glucose transporters - GLUT1 in both tissues and GLUT4 in the frontal cortex. The changes in the prenatally stressed rats were more prominent in the animals that were subjected to stress or glucose loading in adulthood. Conclusion: The increase in carbohydrate brain concentrations evoked by prenatal stress may result from changes in the amounts of glucose transporters, especially GLUT1. Moreover, the obtained results support the hypothesis that stress during the perinatal period permanently increases the sensitivity of brain tissue to factors that act in adulthood.

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment.

The developing and adult brain is a target organ for the vast majority of hormones produced by the body, which are able to cross the blood–brain barrier and bind to their specific receptors on neurons and glial cells. Hormones ensure proper communication between the brain and the body by activating adaptive mechanisms necessary to withstand and react to changes in internal and external conditions by regulating neuronal and synaptic plasticity, neurogenesis and metabolic activity of the brain. The influence of hormones on energy metabolism and mitochondrial function in the brain has gained much attention since mitochondrial dysfunctions are observed in many different pathological conditions of the central nervous system. Moreover, excess or deficiency of hormones is associated with cell damage and loss of function in mitochondria. This review aims to expound on the impact of hormones (GLP-1, insulin, thyroid hormones, glucocorticoids) on metabolic processes in the brain with special emphasis on oxidative phosphorylation dysregulation, which may contribute to the formation of pathological changes. Since the brain concentrations of sex hormones and neurosteroids decrease with age as well as in neurodegenerative diseases, in parallel with the occurrence of mitochondrial dysfunction and the weakening of cognitive functions, their beneficial effects on oxidative phosphorylation and expression of antioxidant enzymes are also discussed.