Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis.

The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.

Intrathecal adrenomedullin modulates acute inflammatory pain in the rat formalin test.

Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pronociceptive mediator. This study was undertaken to investigate the role of AM in acute inflammatory pain induced by formalin injection in rats. Interestingly Cerebrospinal fluid (CSF) levels of AM increased 45 min after formalin injection and a selective AM receptor antagonist, AM22-52, administered intrathecally (i.t.) decreased phase 2 flinching in a dose-dependent manner but not phase 1 flinching during the formalin test. This anti-hyperalgesic effect of i.t. AM22-52 lasted for 4 h or more. AM in the CSF contributes to the modulation of acute inflammatory pain in the formalin test, and blocking downstream signaling effects of the AM receptor has the potential to relieve pain associated with acute inflammation.

Adrenomedullin concentration in the cerebrospinal fluid is related to appetite loss and delayed ischemic neurological deficits after subarachnoid hemorrhage.

OBJECTIVE: Adrenomedullin (AM) is secreted into the cerebrospinal fluid (CSF) from the choroid plexus and regulates appetite. Adrenomedullin concentration in the CSF is elevated 7-10 days after the onset of aneurysmal subarachnoid hemorrhage (SAH). The aim of the present study was to determine whether CSF AM concentration is related to appetite and delayed ischemic neurological deficits (DIND) after SAH. METHODS: Adrenomedullin concentration in the CSF, blood plasma profile, and appetite status were measured in 22 patients with SAH who underwent aneurysmal clipping within 48 hours of SAH onset. Appetite status was measured using dietary oral calorie intake and self-reported appetite level. All outcome variables were measured at an early (Day 3) and late (Day 8) time point after SAH onset (Day 0). RESULTS: Dietary oral calorie intake (P = 0·02), self-reported appetite level (P = 0·03), hemoglobin (P = 0·01), albumin (P = 0·03), glucose (P = 0·01), and insulin (P = 0·03) levels were lower at the late time point than at the early time point. Cerebrospinal fluid adrenomedullin concentration was higher at the late time point than at the early time point (P = 0·0007). There was a significant negative correlation between AM concentration and dietary oral calorie intake (r = -0·478, P = 0·024) and self-reported appetite level (r = -0·454, P = 0·033) at the late time point. Six patients (27%) developed DIND. Adrenomedullin concentration at the late time point was significantly higher in patients who developed DIND than in patients who did not (P = 0·02). CONCLUSIONS: Cerebrospinal fluid adrenomedullin concentration 8 days after SAH onset is related to appetite loss and DIND.

Impaired cerebral blood flow autoregulation during posttraumatic arterial hypotension after fluid percussion brain injury is prevented by phenylephrine in female but exacerbated in male piglets by extracellular signal-related kinase mitogen-activated protein kinase upregulation.

OBJECTIVE: Traumatic brain injury contributes to morbidity and mortality in children and boys are disproportionately represented. Hypotension is common and worsens outcome after traumatic brain injury. Extracellular signal-related kinase mitogen-activated protein kinase is upregulated and reduces cerebral blood flow after fluid percussion brain injury in piglets. We hypothesized that increased cerebral perfusion pressure through phenylephrine sex dependently reduces impairment of cerebral autoregulation during hypotension after fluid percussion brain injury through modulation of extracellular signal-related kinase mitogen-activated protein kinase. DESIGN: Prospective, randomized animal study. SETTING: University laboratory. SUBJECTS: Newborn (1- to 5-day-old) pigs. INTERVENTIONS: Cerebral blood flow, pial artery diameter, intracranial pressure, and autoregulatory index were determined before and after fluid percussion brain injury in untreated, preinjury, and postinjury phenylephrine (1 microg/kg/min intravenously) treated male and female pigs during normotension and hemorrhagic hypotension. Cerebrospinal fluid extracellular signal-related kinase mitogen-activated protein kinase was determined by enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: Reductions in pial artery diameter, cerebral blood flow, cerebral perfusion pressure, and elevated intracranial pressure after fluid percussion brain injury were greater in males, which were blunted by phenylephrine pre- or postfluid percussion brain injury. During hypotension and fluid percussion brain injury, pial artery dilation was impaired more in males. Phenylephrine decreased impairment of hypotensive pial artery dilation after fluid percussion brain injury in females, but paradoxically caused vasoconstriction after fluid percussion brain injury in males. Papaverine-induced pial artery vasodilation was unchanged by fluid percussion brain injury and phenylephrine. Cerebral blood flow, cerebral perfusion pressure, and autoregulatory index decreased markedly during hypotension and fluid percussion brain injury in males but less in females. Phenylephrine prevented reductions in cerebral blood flow, cerebral perfusion pressure, and autoregulatory index during hypotension in females but increased reductions in males. Cerebrospinal fluid extracellular signal-related kinase mitogen-activated protein kinase was increased more in males than females after fluid percussion brain injury. Phenylephrine blunted extracellular signal-related kinase mitogen-activated protein kinase upregulation in females but increased extracellular signal-related kinase mitogen-activated protein kinase upregulation in males after fluid percussion brain injury. CONCLUSIONS: These data indicate that elevation of cerebral perfusion pressure with phenylephrine sex dependently prevents impairment of cerebral autoregulation during hypotension after fluid percussion brain injury through modulation of extracellular signal-related kinase mitogen-activated protein kinase. These data suggest the potential role for sex-dependent mechanisms in cerebral autoregulation after pediatric traumatic brain injury.

Cerebrospinal fluid adrenomedullin concentration correlates with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage.

BACKGROUND: Adrenomedullin (AM), a vasorelaxant peptide, is secreted into the cerebrospinal fluid (CSF) from the choroid plexus and can exert natriuretic effects in the kidney. CSF AM concentration is elevated 7-10 days after the onset of aneurysmal subarachnoid hemorrhage (SAH). The aim of the present study was to determine whether CSF AM concentrations correlate with hyponatremia and delayed ischemic neurological deficits (DIND) after SAH. METHODS: CSF and plasma concentrations of AM, brain natriuretic peptide, and atrial natriuretic peptide concentrations were measured in 32 patients with SAH who underwent aneurysmal clipping within 48 h of onset. CSF and blood samples were obtained from these patients during the early period (days 1-3, day 0 being regarded as the day of SAH onset) and the late period (days 8-10). RESULTS: In all patients, AM concentration during the early and late periods was significantly higher in the CSF than in the plasma (p = 0.0028 and p < 0.0001). In addition, CSF AM concentration was significantly higher during the late period than during the early period (p < 0.0001). Hyponatremia (plasma sodium <135 mmol/l) was present in 11 patients (34.4%) during the late period, and DIND developed in 6 patients (19%) between day 5 and day 13. Logistic regression analysis demonstrated that late-period CSF AM concentration correlated with hyponatremia and DIND (95% CI: 1.003-1.069, p = 0.0074 and 95% CI: 1.003-1.052, p = 0.0108). CONCLUSIONS: The present study demonstrated that CSF AM during the late period following SAH correlates with hyponatremia and DIND.

Increased adrenomedullin concentration in cerebrospinal fluid in patients with septic shock.

Plasma level of adrenomedullin (AM), a potent vasodilator peptide, is increased in patients with sepsis. AM was also found to be present in cerebrospinal fluid (CSF) of humans, and intracerebroventricular injection of AM resulted in elevated systemic blood pressure in rats. In the present study, we measured AM levels in CSF and plasma of 7 patients with septic shock who had severe hypotension, and compared with those of 10 control patients receiving primary transurethral resection of bladder tumor. CSF samples were obtained through the procedure of lumbar puncture and AM levels were measured by radioimmunoassay. AM concentration in CSF of the septic patients was increased to a level 35 times higher than that of control group (35 +/- 21 vs. 0.9 +/-0 .3 pmol/L, mean +/- S .D., p < 0.01). Similarly, plasma AM concentration was increased by 27 times compared with control group (176 +/- 71 vs. 6.5+/-1.8 pmol/L, p < 0.01). Despite the similar increase in CSF and plasma AM, no significant correlation was found between the AM concentrations in the CSF and plasma (r = 0.01 P = 0.95). Taken together with the central actions of AM, these findings suggest that AM of the central nervous system may be involved in pathophysiology of sepsis of humans.