Effects of growth hormone in the central nervous system

ABSTRACT Growth hormone (GH) is best known for its effect stimulating tissue and somatic growth through the regulation of cell division, regeneration and proliferation. However, GH-responsive neurons are spread over the entire central nervous system, suggesting that they have important roles in the brain. The objective of the present review is to summarize and discuss the potential physiological importance of GH action in the central nervous system. We provide evidence that GH signaling in the brain regulates the physiology of numerous functions such as cognition, behavior, neuroendocrine changes and metabolism. Data obtained from experimental animal models have shown that disruptions in GH signaling in specific neuronal populations can affect the reproductive axis and impair food intake during glucoprivic conditions, neuroendocrine adaptions during food restriction, and counter-regulatory responses to hypoglycemia, and they can modify gestational metabolic adaptions. Therefore, the brain is an important target tissue of GH, and changes in GH action in the central nervous system can explain some dysfunctions presented by individuals with excessive or deficient GH secretion. Furthermore, GH acts in specific neuronal populations during situations of metabolic stress to promote appropriate physiological adjustments that restore homeostasis. Arch Endocrinol Metab. 2019;63(6):549-56

Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy

A ketogenic diet is an important therapy used in the control of drug-refractory seizures. Many studies have shown that children and adolescents following ketogenic diets exhibit an over 50% reduction in seizure frequency, which is considered to be clinically relevant. These benefits are based on a diet containing high fat (approximately 90% fat) for 24 months. This dietary model was proposed in the 1920s and has produced variable clinical responses. Previous studies have shown that the mechanisms underlying seizure control involve ketone bodies, which are produced by fatty acid oxidation. Although the pathways involved in the ketogenic diet are not entirely clear, the main effects of the production of ketone bodies appear to be neurotransmitter modulation and antioxidant effects on the brain. This review highlights the impacts of the ketogenic diet on the modulation of neurotransmitters, levels of biogenic monoamines and protective antioxidant mechanisms of neurons. In addition, future perspectives are proposed. .

Analysis of the NMDA in focal cerebral ischemia in rats / Análisis del NMDA en isquemia cerebral focal en ratas

NMDAR (N-methyl-D-aspartate receptor) is one subtype of ionotrophic glutamate receptor which is extensively distributed in the central nervous system (CNS). In the mammalian CNS, NMDAR serves prominent roles in the pathophysiologic process of cerebral ischemia. This study aimed to investigate the pattern of expression of protein and gene of the excitatory neurotransmitter NMDAR in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. 120 rats were randomly divided into 6 groups (20 animals each): control - no surgery; sham - simulation of surgery; ischemic - focal ischemia for 1 hour, without reperfusion; ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. Ten animals from each experimental group were used to establish the volume of infarct. Transient focal cerebral ischemia was obtained in rats by occlusion of the middle cerebral artery with an intraluminal suture. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the protein and gene NMDA were evaluated by immunohistochemistry and quantitative real-time PCR, respectively. Increases in the protein and gene NMDA receptor in the ischemics areas were observed and these increases were reduced by hypothermia and ketoprofen. The increase in the NMDA receptor protein and gene expression observed in the ischemic animals was reduced by neuroprotection (hypothermia and ketoprofen). The NMDA receptor increases in the ischemic area suggests that the NMDA mediated neuroexcitotoxicity plays an important role in cell death and that the neuroprotective effect of both, hypothermia and ketoprofen is directly involved with the NMDA...

NMDAR (N-metil-D-aspartato) es un tipo de receptor de glutamato ionotrópico y está ampliamente distribuido en el sistema nervioso central (SNC). En el SNC de mamíferos, NMDAR se destaca de manera importante en el proceso fisiopatológico de la isquemia cerebral. Este estudio tuvo como objetivo investigar el patrón de expresión de proteínas y genes para el NMDA neurotransmisor excitatorio experimental de la isquemia cerebral focal y el vacío en la neuroprotección con hipotermia y ketoprofeno. Se dividieron 120 ratas aleatoriamente en grupos de 6 animales cada uno (20): Control - sin cirugía; Sham - simulación de cirugía; isquémicas - isquemia focal durante 1 hora, sin reperfusión isquémica; hipotermia intra-isquémica; isquemia; previa aplicación de ketoprofeno intravenoso, e hipotermia isquémica y ketoprofeno. Diez animales de cada grupo experimental fueron utilizados para establecer el volumen de infarto.La isquemia cerebral focal transitoria fue obtenida en ratas mediante oclusión de la arteria cerebral media con una sutura intraluminal. El volumen de infarto fue medido mediante análisis morfométrico de las áreas de infarto definidas por cloruro de trifenil tetrazolio y patrones de expresión de la proteína y el gen de NMDA, fueron evaluados por inmunohistoquímica y PCR cuantitativa en tiempo real, respectivamente. Se observaron aumentos en la proteína y en el gen del receptor de NMDA en las áreas isquémicas y estos aumentos fueron reducidos por la hipotermia y ketoprofeno. El aumento de la proteína del receptor de NMDA y la expresión génica observada en los animales isquémicos fue reducido mediante hipotermia y ketoprofeno. Los aumentos del receptor de NMDA en el área isquémica sugiere que la neuro excitotoxicidad mediada por NMDA desempeña un papel importante en la muerte celular y que el efecto neuroprotector de ambos, hipotermia y ketoprofeno está directamente relacionado al NMDA...

Role of PPAR, a Nuclear Hormone Receptor in Neuroprotection.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. PPAR-alpha is involved in wound healing, stimulation of lipid and folic acid catabolism, inflammation control, inhibition of ureagenesis and peroxisome proliferation. The PPAR/ is involved wound healing, cell proliferation, embryo implantation, adipocyte differentiation, myelination alteration and apoptosis. The PPAR is involved in fat, lipid and calorie utilization, sugar control, inflammation control and macrophage (MQ) matutation. Homocysteine (Hcy) binds to nuclear peroxisome proliferator activated receptor. Increase in PPAR expression decreases the level of nitrotyrosine and increases endothelial nitric oxide concentration, decreases metalloproteinase activity and expression as well as elastinolysis and reverses Hcy-mediated vascular dysfunction. The PPAR initially recognized as a regulator of adipocyte development has become a potential therapeutic target for the treatment of diverse disorders. In addition, the activation of PPAR receptor ameliorates neurodegenerative disease. This review focuses on the recent knowledge of PPAR in neuroprotection and deals with the mechanism of neuroprotection of central nervous system disorder by PPAR.

Neuroprotección mediada por BDNF y óxido nítrico frente a excitotoxicidad en neuronas corticales e hipocampales / BDNF and nitric oxide-mediated neuroprotection against excitotoxicity in cortical and hippocampal neurons

En la epilepsia del lóbulo temporal (ELT), el hipocampo y estructuras temporales adyacentes se convierten en foco epiléptico, lo que ocurre después de un insulto cerebral, como una convulsión prolongada (o Status Epilepticus [SE]). Posterior al insulto, en el hipocampo ocurre muerte neuronal por excitotoxicidad, es decir, por sobre estimulación de receptores glutamatérgicos tipo NMDA (R-NMDA) y síntesis de óxido nítrico (NO) por la óxido nítrico sintasa neuronal (nNOS), una enzima dependiente de calcio. Sin embargo, otras estructuras cerebrales, como la corteza cerebral, son más resistentes al daño excitotóxico. Postulamos que esta menor susceptibilidad de la corteza cerebral a la excitotoxicidad, se debería a neuroprotección dependiente de la neurotrofina BDNF, que se sabe estimula la sobrevida neuronal. Se utilizaron cultivos neuronales primarios de hipocampo y corteza cerebral. Para evaluar excitotoxicidad, se agregó NMDA 30 uM. Se utilizaron estrategias farmacológicas para poner a prueba esta hipótesis, como el uso de L-NNA (inhibidor NOS), y TrkB-Fc (atrapador de BDNF). Se evaluó el porcentaje de sobrevida celular mediante el test de exclusión de Azul de Tripán. La viabilidad de los cultivos después de agregar NMDA fueron: corticales 71,2 +/- 2,8 por ciento, hipocampales 24,6 +/- 2,2 por ciento (p<0,01). Al inhibir la NOS, la viabilidad fue: corticales 31 +/- 6,5 por ciento, hipocampales 79,2 +/- 5,4 por ciento (p<0,01). En ausencia de BDNF fue: corticales 28,7+/- 7,9 por ciento, hipocampales 88,9 +/- 3 por ciento (p<0,01). Concluimos que después de un insulto excitotóxico, BDNF/NO son neuroprotectores en neuronas corticales pero no hipocampales. La potenciación de mecanismos neuroprotectores podría ser una alternativa terapéutica en patologías que involucran muerte neuronal por excitotoxicidad.

In temporal-lobe epilepsy (TLE), the hippocampus and adjacent temporal structures become an epileptic focus following a brain insult, such as a prolonged seizure (or Status Epilepticus). After the insult, neuronal death by excitotoxicity ocurrs, this is, by over stimulation of NMDA-type glutamate receptors (R-NMDA) and nitric oxide sinthesis by neuronal nitric oxide synthase (nNOS), a calcium-dependant enzyme. However, other brain structures, such as the cerebral cortex, are much more resistant to an excitotoxic challenge. We propose that the decreased susceptibility of the cerebral cortex could be explained by neuroprotection mediated by the neurotrophin BDNF, which is known to stimulate neuronal survival. Primary hippocampal and cortical neuronalcultures were used. To evaluate excitotoxicity, 30 uM NMDA was added. The signaling pathways to be tested were inhibited by using pharmacological inhibitors: L-NNA (NOS inhibitor), and TrkB-Fc, a BDN-scavenger. Percentages of cellular survival were evaluated using the Trypan Blue exclusion test. The viability of the cultures after adding NMDA was: larger in cortical than in hippocampal cultures, 71,2 +/- 2,8 percent for cortical and 24,6 +/- 2,2 percent hippocampal cells (p<0,01). When inhibiting NOS, the viability was: 31 +/- 6,5 percent for cortical and 79,2 +/- 5,4 percent for hippocampal cells (p<0,01). In absence of BDNF, 28,7 +/- 7,9 percent of the cortical cells survived, while in the hippocampal cultures it was of 88,9 +/- 3 percent (p<0,01). We conclude that after an excitotoxic insult, BDNF/NO are neuroprotective in cortical but not hippocampal neurons. The potentiation of such neuroprotective mecanisms could be used as a therapeutic alternative in pathologies that involve neuronal death by excitotoxicity.

PAF antagonism modifies neuroprotective action of histone deacetylase and calcineurin phosphatase inhibitors in mice.

To evaluate the hypothesis that platelet activating factor (PAF) antagonism may affect the functional recovery following the nerve injuries and also to evaluate the effect of PAF receptor antagonism on the neuroprotective effect of tacrolimus and sodium valproate, effect of PAF receptor antagonist, WEB2086 was evaluated in animal models of sciatic nerve crush and endothelin-1 induced focal cerebral ischemia. WEB2086, per se, while attenuating spontaneous sensory motor recovery after sciatic nerve crush, enhanced functional recovery after focal cerebral ischemia. WEB2086 also attenuated the neuroprotective effect of tacrolimus and sodium valproate subsequent to peripheral nerve injury, while it significantly improved the neuroprotective action of tacrolimus and sodium valproate following cerebral ischemia reperfusion injury. These results suggest that PAF receptor antagonists alone and in combination with tacrolimus/sodium valproate could be used in the treatment of cerebral ischemia reperfusion injuries however, their use following peripheral nerve injuries could be detrimental.

Estrogen enhances the inhibitory effect of iron on microglial nitric oxide production.

Abnormal iron accumulation has been consistently reported in specific brain regions of many neurodegenerative diseases. At cellular level, iron is unusually observed in microglia, immune effector cell of the brain. Most evidence has provided that upon activation, microglia produces neurotoxins and different kinds of inflammatory mediators. Therefore, it is believed that activated microglia is actively involved in neurodegenerative process. Using a rat microglial cell line (HAPI), the present study was designed to address the role of iron for immune function of microglia, in particular, the production of Nitric Oxide (NO) in the presence or absence of estrogen, a potential neuroprotective agent. The present results demonstrated that exposure of microglia to iron significantly decreased lipopolysaccaride-induced NO production, as determined by nitrite accumulation in the cell culture medium, and such effect of iron was potentiated by increasing concentration of estrogen. Transcript analysis revealed that estrogen, but not iron, decreased the expression of inducible Nitric Oxide Synthase (iNOS). These results demonstrate that estrogen enhances the inhibitory effect of iron on microglial NO production by decreasing mRNA expression of iNOS and also suggest that iron sequestration by microglia under neuropathological conditions could be a protective mechanism against NO-induced neurotoxicity.