Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice.

Traumatic brain injury is a leading cause of hypopituitarism, which compromises patients' recovery, quality of life, and life span. To date, there are no means other than standardized animal studies to provide insights into the mechanisms of posttraumatic hypopituitarism. We have found that GH levels were impaired after inducing a controlled cortical impact (CCI) in mice. Furthermore, GHRH stimulation enhanced GH to lower level in injured than in control or sham mice. Because many characteristics were unchanged in the pituitary glands of CCI mice, we looked for changes at the hypothalamic level. Hypertrophied astrocytes were seen both within the arcuate nucleus and the median eminence, two pivotal structures of the GH axis, spatially remote to the injury site. In the arcuate nucleus, GHRH neurons were unaltered. In the median eminence, injured mice exhibited unexpected alterations. First, the distributions of claudin-1 and zonula occludens-1 between tanycytes were disorganized, suggesting tight junction disruptions. Second, endogenous IgG was increased in the vicinity of the third ventricle, suggesting abnormal barrier properties after CCI. Third, intracerebroventricular injection of a fluorescent-dextran derivative highly stained the hypothalamic parenchyma only after CCI, demonstrating an increased permeability of the third ventricle edges. This alteration of the third ventricle might jeopardize the communication between the hypothalamus and the pituitary gland. In conclusion, the phenotype of CCI mice had similarities to the posttraumatic hypopituitarism seen in humans with intact pituitary gland and pituitary stalk. It is the first report of a pathological status in which tanycyte dysfunctions appear as a major acquired syndrome.

Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension.

RATIONALE: We have previously found that T lymphocytes are essential for development of angiotensin II-induced hypertension; however, the mechanisms responsible for T-cell activation in hypertension remain undefined. OBJECTIVE: We sought to study the roles of the CNS and pressure elevation in T-cell activation and vascular inflammation caused by angiotensin II. METHODS AND RESULTS: To prevent the central actions of angiotensin II, we created anteroventral third cerebral ventricle (AV3V) lesions in mice. The elevation in blood pressure in response to angiotensin II was virtually eliminated by AV3V lesions, as was activation of circulating T cells and the vascular infiltration of leukocytes. In contrast, AV3V lesioning did not prevent the hypertension and T-cell activation caused by the peripheral acting agonist norepinephrine. To determine whether T-cell activation and vascular inflammation are attributable to central influences or are mediated by blood pressure elevation, we administered hydralazine (250 mg/L) in the drinking water. Hydralazine prevented the hypertension and abrogated the increase in circulating activated T cells and vascular infiltration of leukocytes caused by angiotensin II. CONCLUSIONS: We conclude that the central and pressor effects of angiotensin II are critical for T-cell activation and development of vascular inflammation. These findings also support a feed-forward mechanism in which modest degrees of blood pressure elevation lead to T-cell activation, which in turn promotes inflammation and further raises blood pressure, leading to severe hypertension.

Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS.

The habenular-interpeduncular pathway is involved in the modulation of several functions including neuroendocrine and stress responses. Interleukin-18 (IL-18) is a pro-inflammatory cytokine predominantly studied as a modulator of immune functions and also produced in the adrenal cortex following activation of the hypothalamic-pituitary-adrenal axis. In the central nervous system, IL-18 was demonstrated to induce sleep and to influence long-term potentiation and was proposed to mediate local inflammatory reactions. The present study investigated the localization of IL-18 and its expression following either acute or chronic restraint stress in the brain of adult male Wistar rats. Using immunocytochemistry and in situ hybridization we report the unprecedented localization of IL-18 in the neurons of the superior part of the medial habenula (MHbS), their projections to the interpenducular nucleus and its expression in the ependymal cells surrounding the third and the lateral ventricles. In addition, acute (2 h) or chronic (6 h/day for 3 weeks) restraint stress induced a strong elevation of IL-18 immunostaining in the MHbS but not in ependymal cells. The present data suggest that IL-18 may participate in the modulation of stress responses in the MHbS. They also suggest that ependymal cells may be the source of IL-18 previously reported in the cerebrospinal fluid (CSF). The role of IL-18 in the ependyma and the CSF remains to be elucidated.