Role of glucocorticoids in mediating effects of fasting and diabetes on hypothalamic gene expression.

BACKGROUND: Fasting and diabetes are characterized by elevated glucocorticoids and reduced insulin, leptin, elevated hypothalamic AGRP and NPY mRNA, and reduced hypothalamic POMC mRNA. Although leptin replacement can reverse changes in hypothalamic gene expression associated with fasting and diabetes, leptin also normalizes corticosterone; therefore the extent to which the elevated corticosterone contributes to the regulation of hypothalamic gene expression in fasting and diabetes remains unclear. To address if elevated corticosterone is necessary for hypothalamic responses to fasting and diabetes, we assessed the effects of adrenalectomy on hypothalamic gene expression in 48-hour-fasted or diabetic mice. To assess if elevated corticosterone is sufficient for the hypothalamic responses to fasting and diabetes, we assessed the effect of corticosterone pellets implanted for 48 hours on hypothalamic gene expression. RESULTS: Fasting and streptozotocin-induced diabetes elevated plasma glucocorticoid levels and reduced serum insulin and leptin levels. Adrenalectomy prevented the rise in plasma glucocorticoids associated with fasting and diabetes, but not the associated reductions in insulin or leptin. Adrenalectomy blocked the effects of fasting and diabetes on hypothalamic AGRP, NPY, and POMC expression. Conversely, corticosterone implants induced both AGRP and POMC mRNA (with a non-significant trend toward induction of NPY mRNA), accompanied by elevated insulin and leptin (with no change in food intake or body weight). CONCLUSION: These data suggest that elevated plasma corticosterone mediate some effects of fasting and diabetes on hypothalamic gene expression. Specifically, elevated plasma corticosterone is necessary for the induction of NPY mRNA with fasting and diabetes; since corticosterone implants only produced a non-significant trend in NPY mRNA, it remains uncertain if a rise in corticosterone may be sufficient to induce NPY mRNA. A rise in corticosterone is necessary to reduce hypothalamic POMC mRNA with fasting and diabetes, but not sufficient for the reduction of hypothalamic POMC mRNA. Finally, elevated plasma corticosterone is both necessary and sufficient for the induction of hypothalamic AGRP mRNA with fasting and diabetes.

Cardiovascular responses evoked by carbachol microinjection into the posterior hypothalamus involves ganglionic nicotinic and muscarinic mechanisms.

1. Microinjection of the cholinergic agonist carbachol (3.3, 5.5 and 13.2 nmol) into the posterior hypothalamic nucleus of conscious rats evokes a dose-dependent increase in blood pressure. The pressor response evoked by the lower doses of carbachol was attenuated by pretreatment with the ganglionic nicotinic receptor antagonist pentolinium (10 mg kg(-1), i.v.) while blockade of V1-vasopressin receptors with [d(CH2)5Tyr(Me)]AVP (20 microg kg(-1), i.v.) reduced the pressor response evoked by the highest dose. 2. The combination of pentolinium and the muscarinic receptor antagonist methylatropine (2 mg kg(-1), i.v.) completely blocked the response evoked by the lower doses while the addition of [d(CH2)5Tyr(Me)]AVP to these two antagonists was required for further inhibition of the pressor response to the highest dose of carbachol. Bilateral adrenal demedullation did not affect the pressor response evoked by 5.5 or 13.2 nmol of carbachol. 3. Treatment of intact and adrenal demedullated rats with pentolinium after the pressor response to 13.2 nmol of carbachol was underway reversed the pressor response, but not to the same degree as that provided by the combination of pentolinium and methylatropine, or pentolinium and [d(CH2)5Tyr(Me)]AVP. 4. Methylatropine or [d(CH2)5Tyr(Me)]AVP caused a slight reversal of the carbachol-induced pressor response once it was underway in intact rats. Methylatropine given before or after pentolinium worked with the pentolinium to completely reverse the response. Methylatropine given alone reversed the bradycardia evoked by carbachol to a tachycardia which itself was antagonized by subsequent treatment with pentolinium. 5. These results suggest that the pressor response evoked by carbachol microinjection into the posterior hypothalamic nucleus of conscious rats involves sympathoexcitation and vasopressin release. The sympathoexcitation involves nicotinic and muscarinic receptors in autonomic ganglia.

Effect of adrenal medullectomy on responses in heat production, plasma catecholamines and body temperature of burned rats to changes in the temperature of the hypothalamus.

Burn (B) and control (C) rats with and without adrenal medullectomy (Adx) 9-11 days postburn underwent warning and cooling of the preoptic anterior hypothalamus (POAH) during calorimetry at 22 degrees and 28 degrees C ambient. Blood was drawn for catecholamine assay during each displacement of the POAH temperature (Thy). The heat production (Hp) for the AdxB group at 22 degrees and 28 degrees C was not different from the Hp for the sham AdxB group (80 +/- 4 vs 86 +/- 8 at 22 degrees C, 58 +/- 8 vs 64 +/- 7 W/m2 at 28 degrees C) in spite of there being no detectable circulating epinephrine (E) for the AdxB groups. Cooling of the POAH of the AdxB 22 degrees C group, however, did not induce a further increment in Hp, in contrast to all other groups. Thy demonstrated good significant negative linear correlation with Hp for all groups. The resulting slopes were not significantly different from one another, indicating no difference in thermal sensitivity of the POAH between the groups. In four of eight groups plasma norepinephrine (NE) demonstrated positive correlation with Hp and in five of eight groups negative correlation with Thy, Plasma E values did not correlate with Hp and demonstrated negative correlation with Thy in two of four possible groups. These data show that postburn hypermetabolism is not dependent on E in the rat and suggest that NE may be calorigenic in burned rats.

Tratamiento médico y quirúrgico de la enfermedad de Parkinson: estudio a largo plazo / Medical and surgical treatment of Parkinson's disease. A long term study

Este trabajo estudia los efectos del tratamiento médico y quirúrgico sobre el curso natural de la enfermedad de Parkinson. Tres grupos de pacientes fueron estudiados: I. Pacientes tratados con levodopa/carbidopa y anticolinérgicos (n = 10). II. Pacientes tratados con talamotomía (n = 9). III. Pacientes con tratamiento médico más trasplante autólogo de médula adrenal al núcleo caudado (n = 8). Fueron evaluados antes de iniciar el tratamiento médico o de efectuar la cirugía, al mes, a los seis meses y al año. Fueron usadas las escalas clínicas: New York Parkinson's Disease Scale, Unified Parkinson's Disease Scale, Schwab and England y Hoehn and Yarth Scale. Se evaluó por separado temblor, rigidez, bradicinesia y deterioro mental. Se uso un análisis de varianza tipo Friedman. Grupo I. No hubo mejoría significativa y sí un deterioro mental significativo al año. Grupo II. Hubo mejoría significativa del temblor y la rigidez, sin embargo el deterioro mental al año determinó un empeoramiento de la escala global. Grupo III. No hubo mejoría significativa, pero el deterioro al año fue menos pronunciado que para los otros grupos

The effect of intrahypothalamic injection of homodimaprit on blood pressure.

Bilateral injection of the inhibitor of histamine-N-methyltransferase, SKF 91488, which is also known as homodimaprit (5 micrograms), into the preoptic area of the rat produced delayed hypertension, tachycardia and hyperthermia. Some animals exhibited pulmonary edema. These effects were only noted 18-24 hr after an injection and were not an artifact of the injection, since the administration of artificial cerebrospinal fluid produced none of these effects. At the time noted, lesions of the rostral hypothalamus, including the preoptic area, were evident. Injection of a vasopressin antagonist, intravenously, did not lower the blood pressure of the hypertensive animals nor did previous bilateral adrenal demullation prevent or delay the hypertension or tachycardia. Therefore, it does not appear that hypersecretion of either vasopressin or adrenal catecholamines contributed to the cardiovascular effects. Peripheral pretreatment with the sympathetic neurotoxin 6-hydroxydopamine however, did prevent the delayed rise in blood pressure following an injection of homodimaprit. From these studies, it is concluded that the injection of homodimaprit produces lesions in the preoptic area, resulting in hypertension that is maintained by excessive activation of the sympathetic nervous system.