The taste of neuroinflammation: Molecular mechanisms linking taste sensing to neuroinflammatory responses.

Evidence indicates a critical role of neuroinflammatory response as an underlying pathophysiological process in several central nervous system disorders, including neurodegenerative diseases. However, the molecular mechanisms that trigger neuroinflammatory processes are not fully known. The discovery of bitter taste receptors in regions other than the oral cavity substantially increased research interests on their functional roles in extra-oral tissues. It is now widely accepted that bitter taste receptors, for instance, in the respiratory, intestinal, reproductive and urinary tracts, are crucial not only for sensing poisonous substances, but also, act as immune sentinels, mobilizing defense mechanisms against pathogenic aggression. The relatively recent discovery of bitter taste receptors in the brain has intensified research investigation on the functional implication of cerebral bitter taste receptor expression. Very recent data suggest that responses of bitter taste receptors to neurotoxins and microbial molecules, under normal condition, are necessary to prevent neuroinflammatory reactions. Furthermore, emerging data have revealed that downregulation of key components of the taste receptor signaling cascade leads to increased oxidative stress and inflammasome signaling in neurons that ultimately culminate in neuroinflammation. Nevertheless, the mechanisms that link taste receptor mediated surveillance of the extracellular milieu to neuroinflammatory responses are not completely understood. This review integrates new data on the molecular mechanisms that link bitter taste receptor sensing to neuroinflammatory responses. The role of bitter taste receptor-mediated sensing of toxigenic substances in brain disorders is also discussed. The therapeutic significance of targeting these receptors for potential treatment of neurodegenerative diseases is also highlighted.

Neuropathophysiology of coronavirus disease 2019: neuroinflammation and blood brain barrier disruption are critical pathophysiological processes that contribute to the clinical symptoms of SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is caused by the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) first discovered in Wuhan, Hubei province, China in December 2019. SARS-CoV-2 has infected several millions of people, resulting in a huge socioeconomic cost and over 2.5 million deaths worldwide. Though the pathogenesis of COVID-19 is not fully understood, data have consistently shown that SARS-CoV-2 mainly affects the respiratory and gastrointestinal tracts. Nevertheless, accumulating evidence has implicated the central nervous system in the pathogenesis of SARS-CoV-2 infection. Unfortunately, however, the mechanisms of SARS-CoV-2 induced impairment of the central nervous system are not completely known. Here, we review the literature on possible neuropathogenic mechanisms of SARS-CoV-2 induced cerebral damage. The results suggest that downregulation of angiotensin converting enzyme 2 (ACE2) with increased activity of the transmembrane protease serine 2 (TMPRSS2) and cathepsin L in SARS-CoV-2 neuroinvasion may result in upregulation of proinflammatory mediators and reactive species that trigger neuroinflammatory response and blood brain barrier disruption. Furthermore, dysregulation of hormone and neurotransmitter signalling may constitute a fundamental mechanism involved in the neuropathogenic sequelae of SARS-CoV-2 infection. The viral RNA or antigenic peptides also activate or interact with molecular signalling pathways mediated by pattern recognition receptors (e.g., toll-like receptors), nuclear factor kappa B, Janus kinase/signal transducer and activator of transcription, complement cascades, and cell suicide molecules. Potential molecular targets and therapeutics of SARS-CoV-2 induced neurologic damage are also discussed.

Stress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways.

Stress is a nonspecific response to a threat or noxious stimuli with resultant damaging consequences. Stress is believed to be an underlying process that can trigger central nervous system disorders such as depression, anxiety, and post-traumatic stress disorder. Though the pathophysiological basis is not completely understood, data have consistently shown a pivotal role of inflammatory mediators and hypothalamo-pituitary-adrenal (HPA) axis activation in stress induced disorders. Indeed emerging experimental evidences indicate a concurrent activation of inflammatory signaling pathways and not only the HPA axis, but also, peripheral and central renin-angiotensin system (RAS). Furthermore, recent experimental data indicate that the HPA and RAS are coupled to the signaling of a range of central neuro-transmitter, -mediator and -peptide molecules that are also regulated, at least in part, by inflammatory signaling cascades and vice versa. More recently, experimental evidences suggest a critical role of stress in disruption of the blood brain barrier (BBB), a neurovascular unit that regulates the movement of substances and blood-borne immune cells into the brain parenchyma, and prevents peripheral injury to the brain substance. However, the mechanisms underlying stress-induced BBB disruption are not exactly known. In this review, we summarize studies conducted on the effects of stress on the BBB and integrate recent data that suggest possible molecular mechanisms and signaling pathways underlying stress-induced BBB disruption. Key molecular targets and pharmacological candidates for treatment of stress and related illnesses are also summarized.

Role of the Autonomic Nervous System and Vascular Endothelial Factors in the Development of Primary Arterial Hypotension in Paediatric Patients.

BACKGROUND: There is a dearth and inconsistency of data on the role of the autonomic nervous system (ANS) in the development of arterial hypotension. Also, little is known about the involvement of endothelial factors in the development of this disease. The aim of the study was to investigate the role of the ANS and endothelial factors or vasoregulators in the development of primary arterial hypotension (PAH) in children. METHODS: The cardiointervalography and clino-orthostatic test results of 113 children with PAH were compared with 88 healthy children of comparable age (7-11 years). Serum endothelial factors (nitric oxide and endothelins) of all children were measured. RESULTS: The findings revealed that children with PAH had higher activity of the sympathetic (p<0.001) and parasympathetic (p<0.001) divisions of the ANS at the initial (resting) position of clino-orthostatic test. The activity of these divisions of the autonomic nervous system correlated with the activity of a cardiac pacemaker. The change of position from horizontal into vertical was accompanied by a rise only in sympathetic activity (p<0.001). However, there was a decline in the sympathetic nervous system (p<0.001) compared to the indices of the initial (resting) position registered in the tenth minute of the vertical position. The parasympathetic division of the ANS based on heart rate variability showed high activity in all positions of the clino-orthostatic test in the patients with PAH compared with healthy children. The activity of the parasympathetic nervous system was associated with increased synthesis of endothelial factors (nitric oxide and endothelins) in blood. CONCLUSIONS: The inadequate response of the autonomic nervous system to the clino-orthostatic test in children with PAH is associated with disorders of both divisions of the autonomic nervous system as well as vascular endothelial factors.

Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons.

The astrocyte-neuron lactate shunt (ANLS) hypothesis is the most widely accepted model of brain glucose metabolism. However, over the past decades, research has shown that neuronal and astrocyte plasma membrane receptors, in particular, GLUT2, Kir6.2 subunit of the potassium ATP-channel, SGLT-3 acting as glucosensors, play a pivotal role in brain glucose metabolism. Although both ANLS hypothesis and glucosensor model substantially improved our understanding of brain glucose metabolism, the latter appears to be gaining more attention in the scientific community as the former could not account for new research data indicating that hypothalamic and brainstem neurons may not require astrocyte-derived lactate for energy. More recently, emerging evidences suggest a crucial role of sweet taste receptors in brain glucose metabolism. Furthermore, a couple of intracellular molecules acting as glucosensors have been identified in central astrocytes and neurons. This review integrates new data on the mechanisms of brain glucose sensing and metabolism. The role of the glucosensors including the sweet taste T1R2 + T1R3-mediated brain glucose-sensing and metabolism in brain glucose metabolic disorders is discussed. Possible role of glucose sensors (GLUT2, K-ATPKir6.2, SGLT3, T1R2 + T1R3) in brain diseases involving metabolic dysfunctions and the therapeutic significance in targeting central glucosensors for the treatment of these brain diseases are also discussed.

Sweet taste receptor signaling network: possible implication for cognitive functioning.

Sweet taste receptors are transmembrane protein network specialized in the transmission of information from special "sweet" molecules into the intracellular domain. These receptors can sense the taste of a range of molecules and transmit the information downstream to several acceptors, modulate cell specific functions and metabolism, and mediate cell-to-cell coupling through paracrine mechanism. Recent reports indicate that sweet taste receptors are widely distributed in the body and serves specific function relative to their localization. Due to their pleiotropic signaling properties and multisubstrate ligand affinity, sweet taste receptors are able to cooperatively bind multiple substances and mediate signaling by other receptors. Based on increasing evidence about the role of these receptors in the initiation and control of absorption and metabolism, and the pivotal role of metabolic (glucose) regulation in the central nervous system functioning, we propose a possible implication of sweet taste receptor signaling in modulating cognitive functioning.