Estrogen-IGF-1 interactions in neuroprotection: Ischemic stroke as a case study

The steroid hormone 17b-estradiol and the peptide hormone insulin-like growth factor (IGF)-1 independently exert neuroprotective actions in neurologic diseases such as stroke. Only a few studies have directly addressed the interaction between the two hormone systems, however, there is a large literature that indicates potentially greater interactions between the 17b-estradiol and IGF-1 systems. The present review focuses on key issues related to this interaction including IGF-1 and sex differences and common activation of second messenger systems. Using ischemic stroke as a case study, this review also focuses on independent and cooperative actions of estrogen and IGF-1 on neuroprotection, blood brain barrier integrity, angiogenesis, inflammation and post-stroke epilepsy. Finally, the review also focuses on the astrocyte, a key mediator of post stroke repair, as a local source of 17b-estradiol and IGF-1. This review thus highlights areas where significant new research is needed to clarify the interactions between these two neuroprotectants.     

Longitudinal observations of typical English voicing acquisition in a 2-year-old child: Stability of the contrast and considerations for clinical assessment

Early assessment of phonetic and phonological development requires knowledge of typical versus atypical speech patterns, as well as the range of individual developmental trajectories. The nature of data reporting in previous literature on typical voicing acquisition left aspects of the developmental process unclear and limited clinical applicability. This work extends a previous four-month group study to present data for one child over 12 months. Words containing initial /b?p d t/ were elicited from a monolingual English-speaking 2-year-old child biweekly for 25 sessions. Voice onset time (VOT) was measured for each stop. For each consonant and recording session, we measured range as well as accuracy, overshoot and discreteness calculated for means and individual tokens. The results underscore the value of token-by-token analyses. They further reveal that typical development may involve an extended period of fluctuating voicing patterns, suggesting that the voiced/voiceless contrast may take months or years to stabilise.     

Interleukin-1β transfer across the blood–brain barrier in the ovine fetus

Pro-inflammatory cytokines contribute to hypoxic–ischemic brain injury. Blood–brain barrier (BBB) dysfunction represents an important component of hypoxic–ischemic brain injury in the fetus. Hypoxic–ischemic injury could accentuate systemic cytokine transfer across the fetal BBB. There has been considerable conjecture suggesting that systemic cytokines could cross the BBB during the perinatal period. Nonetheless, evidence to support this contention is sparse. We hypothesized that ischemia–reperfusion increases the transfer of systemic interleukin-1β (IL-1β) across the BBB in the fetus. Ovine fetuses at 127 days of gestation were studied 4 hours after 30 minutes of bilateral carotid artery occlusion and compared with a nonischemic group. Recombinant ovine IL-1β protein was expressed from an IL-1β pGEX-2 T vector in E. coli BL-21 cells and purified. The BBB function was quantified in 12 brain regions using a blood-to-brain transfer constant with intravenous ¹²⁵I-radiolabeled IL-1β (¹²⁵I-IL-1β). Interleukin-1β crossed the intact BBB in nonischemic fetuses. Blood-to-brain transport of ¹²⁵I-IL-1β was higher (P<0.05) across brain regions in fetuses exposed to ischemia–reperfusion than nonischemic fetuses. We conclude that systemic IL-1β crosses the intact fetal BBB, and that ischemia–reperfusion increases transfer of this cytokine across the fetal BBB. Therefore, altered BBB function after hypoxia–ischemia facilitates entry of systemic cytokines into the brain of the fetus.     

The TNF-α/NF-κB signaling pathway has a key role in methamphetamine–induced blood–brain barrier dysfunction

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.     

The role of the spleen in ischemic stroke

This opinion piece highlights the scientific literature reporting that the peripheral immune response to ischemic stroke originates from the spleen. Removal of the spleen not only reduces stroke-induced neurodegeneration but also cellular degeneration in the body''s other tissues when exposed to ischemic conditions.     

Cerebrovascular reactivity is increased with acclimatization to 3,454?m altitude

Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO₂ reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAv_mean) CVR was assessed during hyperventilation (hypocapnia) and CO₂ administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26±4 years (mean±s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAv_mean was not altered. Hypercapnic CVR was decreased at HA0 (1.16%±0.16%/mm Hg, mean±s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13%±0.18% and 2.96%±0.10%/mm Hg) and HA22 (3.32%±0.12% and 3.24%±0.14%/mm Hg) compared with SL (1.98%±0.22% and 2.38%±0.10%/mm Hg; P<0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAv_mean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude.     

CD28 superagonist-mediated boost of regulatory T cells increases thrombo-inflammation and ischemic neurodegeneration during the acute phase of experimental stroke

While the detrimental role of non-regulatory T cells in ischemic stroke is meanwhile unequivocally recognized, there are controversies about the properties of regulatory T cells (T_reg). The aim of this study was to elucidate the role of T_reg by applying superagonistic anti-CD28 antibody expansion of T_reg. Stroke outcome, thrombus formation, and brain-infiltrating cells were determined on day 1 after transient middle cerebral artery occlusion. Antibody-mediated expansion of T_reg enhanced stroke size and worsened functional outcome. Mechanistically, T_reg increased thrombus formation in the cerebral microvasculature. These findings confirm that T_reg promote thrombo-inflammatory lesion growth during the acute stage of ischemic stroke.     

Phenylketonuria: brain phenylalanine concentrations relate inversely to cerebral protein synthesis

In phenylketonuria, elevated plasma phenylalanine concentrations may disturb blood-to-brain large neutral amino acid (LNAA) transport and cerebral protein synthesis (CPS). We investigated the associations between these processes, using data obtained by positron emission tomography with l-[1-¹¹C]-tyrosine (¹¹C-Tyr) as a tracer. Blood-to-brain transport of non-Phe LNAAs was modeled by the rate constant for ¹¹C-Tyr transport from arterial plasma to brain tissue (K₁), while CPS was modeled by the rate constant for ¹¹C-Tyr incorporation into cerebral protein (k₃). Brain phenylalanine concentrations were measured by magnetic resonance spectroscopy in three volumes of interest (VOIs): supraventricular brain tissue (VOI 1), ventricular brain tissue (VOI 2), and fluid-containing ventricular voxels (VOI 3). The associations between k₃ and each predictor variable were analyzed by multiple linear regression. The rate constant k₃ was inversely associated with brain phenylalanine concentrations in VOIs 2 and 3 (adjusted R²=0.826, F=19.936, P=0.021). Since brain phenylalanine concentrations in these VOIs highly correlated with each other, the specific associations of each predictor with k₃ could not be determined. The associations between k₃ and plasma phenylalanine concentration, K₁, and brain phenylalanine concentrations in VOI 1 were nonsignificant. In conclusion, our study shows an inverse association between k₃ and increased brain phenylalanine concentrations.