Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury. INTRODUCTIONGlucose is the main energy source in brain. However, under certain conditions other energy substrates such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB) can be used by brain, including the suckling period, 1,2 prolonged fasting, 3 and the ketogenic diet; 4 all these situations are associated with increased KB levels in blood. Several studies have shown that KB can protect the brain against damage associated with diverse neurotoxic insults such as hypoxia, 5 ischemia, 6-8 hypoglycemia, 9,10 and excitotoxicity. 11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect. It has been observed in vitro that AcAc reduces ROS levels induced by glutamate exposure and glycolysis inhibition in cultured neurons, 12,16 and previous in vivo studies have shown that BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain. 10,18 The mechanism underlying the reduction of ROS by BHB has not been elucidated but we have previously reported that KB display a scavenging action of ROS, in particular of the hydoxyl radical ( • OH). 10 The physiologic and the

What is the topic of this review? Both branches of the autonomic nervous system are involved in the regulation of the inflammatory response. We explore how the hypothalamus may influence this process. What advances does it highlight? We analyse how a lipopolysaccharide signal is transmitted to the brain and which areas participate in the response of the brain to lipopolysaccharide. Recent studies show that the hypothalamus can influence the inflammatory response by modifying the autonomic output. The biological clock, the suprachiasmatic nucleus, is integrated into this circuit, putting a time stamp on the intensity of the inflammatory response. The brain is responsible for maintaining homeostasis of the organism, constantly adjusting its output via hormones and the autonomic nervous system to reach an optimal setting in every compartment of the body. Also, the immune system is under strong control of the brain. Apart from the conventional systemic responses evoked by the brain during inflammation, such as hypothalamic-pituitary-adrenal axis activation and the induction of sickness behaviour, the autonomic nervous system is now recognized to exert regulatory effects on the inflammatory response. Both branches of the autonomic nervous system are proposed to influence the inflammatory process. Here, we focus on those areas of the brain that might be involved in sensing inflammatory stimuli, followed by how that sensing could change the output of the autonomic nervous system in order to regulate the inflammatory response. Finally, we will discuss how the defenses of the body against a lipopolysaccharide challenge are organized by the hypothalamus.

In vertebrates, vasopressin (VP), also known as antidiuretic hormone, and oxytocin (OT) are released from the neural lobe of the pituitary gland into the general circulation. The classic hormonal role of OT is to modulate parturition and lactation, 1 whereas VP regulates plasma osmolarity through water and ion excretion. 2 Therefore, despite the sequence similarity between these peptides, they have very welldifferentiated functions.Three G-coupled receptors for VP have been cloned, which account for VP pressor functions (AVPR1a, G q ), antidiuretic functions (AVPR2, G s ) and adrenocorticotrophin-releasing effects (VPR1b,

The autonomic nervous system (ANS) modulates the immune response through the engagement of an anti-inflammatory reflex. There is controversy regarding which efferent branch of the ANS, sympathetic or parasympathetic, downregulates the intensity of the inflammatory response. Furthermore, how information about the immune status of the body reaches the CNS to engage this reflex remains unclear. The present study demonstrates the existence of a liver-spinal axis that conveys early circulating inflammatory information to the CNS in response to lipopolysaccharide (LPS) and serves as the afferent arm of a sympathetic anti-inflammatory reflex. Furthermore, brainstem and spinal cord visceral sensory neurons show a time-of-day-dependent sensitivity to the incoming inflammatory information, in particular, prostaglandins (PG). Consequentially, the liver-spinal axis promotes the retention of tumor necrosis factor α (TNFα) in the liver and spleen during the resting period, resulting in low plasmatic TNFα levels. Consistently, low sensitivity for LPS during the active period promotes the release of TNFα from the organs into the circulation, resulting in high plasmatic TNFα levels. The present novel findings illustrate how the time-of-day-dependent activation of the liver-spinal axis contributes to the daily fluctuations of the inflammatory response.

No abstract