Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood–brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.

Rights, Rationality and Reproduction: Balancing Interests in the Abortion Debate

As medical technology has advanced, so too have our attitudes towards the level of control we can or should expect to have over our procreative capacities. This creates a multidimensional problem for the law and family planning services in terms of access to services – whether to avoid conception or terminate a pregnancy – and the negligent provision of these services. These developments go to the heart of our perception of autonomy. Unsurprisingly, these matters also raise a moral dilemma for the law. Distinctively, discourse in this area is dominated by assertions of subjective moral value; in relation to life, to personal choice and to notions of the archetypal family. Against this, I stress that a model of objective morality can answer these challenging questions and resolve the inherent problems of legal regulation. Therefore, I argue that notions of autonomy must be based on a rational, action-based understanding of what it means to be a ‘moral agent’. I claim that from this we might support a legal standard, based on objective rational morality, which can frame our constitutional norms and our conception of justice in these contentious areas. This paper claims that the current regulation of abortion is outdated and requires radical reform. It proposes a scheme that would shift the choice towards the mother (and the father), remove the unnecessarily broad disability ground and involve doctors having a role of counsel (rather than gatekeeper).