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Research
- Estrogen-mediated neuroprotection and anti-inflammatory effects
in the brain
Several neuro-immune diseases display gender differences; that
is, men and women have different predispositions to these diseases,
suggesting that sex hormones may play a role in their etiology.
Examples of some diseases for which women have a different
incidence than men include the autoimmune disease multiple
sclerosis; Alzheimer's disease, in which estrogens appear to
be neuroprotective and increase cognitive function; and neurodegenerative
diseases such as amyotrophic lateral sclerosis. Further, estrogens
have been found to be protective against brain damage resulting
from oxygen deprivation in both males and females, suggesting
that estrogen may modulate the activity of cells in the brain
that are responsible for producing factors that contribute
to or exacerbate brain damage, following heart attack or stroke.
One such cell type, whose excessive activation has been implicated
in the worsening of brain damage during all of these conditions,
is the microglial cell.
Microglia are phagocytic immune cells that reside in the central nervous
system. They comprise up to 15% of all brain cells, and respond to the
presence of invading pathogens such as bacteria and viruses. In addition
to their roles in the maintenance of normal brain connectivity and function,
they are also integral to the development of the neuropathologies listed
above. Because microglia are among the first cell types to respond to
neuronal injury, upon their activation, they synthesize and secrete
toxic mediators such as oxygen free radicals and numerous cytokines/chemokines,
that when produced in excessive quantities can be toxic to neurons.
The role of estrogen in these inflammatory processes is poorly understood,
however, it is believed to involve the decreased production of inflammatory
cytokines that are involved in the exacerbation of brain damage. The
goals of our research thus center on delineating the anti-inflammatory
effects of estrogen on microglial cell activation at the molecular level,
by dissecting the signal transduction pathways and receptors that are
modulated by estrogen in activated microglial cells. Defining the molecular
mechanisms involved in the estrogen modulation of microglial cell activation
and their production of inflammatory mediators, may lead to the identification
of novel therapeutic targets that can be exploited to minimize the brain
damage ensuing from neurodegenerative diseases and other brain disorders,
to which women are predisposed.
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- Adenine nucleotide modulation of microglial cell function
and signaling events with hypoxia
In the CNS,
nucleotides such as ATP are released from cells by a variety
of methods including exocytosis, release via membrane channels
and regulated release by astrocytes during calcium wave propagation.
Adenine nucleotides are also present in large amounts at sites
of tissue damage and inflammation, and they may thus be critical
regulators of inflammatory microglial cell function during neurodegenerative/inflammatory
CNS dysfunctions. P2 purinergic receptors, the plasma membrane
proteins through which ATP transduces intracellular signals,
are either heterotrimeric G-protein coupled receptors (P2Y) or
ligand-gated non-specific cation channels (P2X). Microglia express
both P2X and P2Y receptors, and our data indicate that receptors
of both subtypes are involved in the modulation of microglial
cell inflammatory capacity. Intracellular signaling pathways,
such as the mitogen-activated protein (MAP) kinases, are potently
stimulated by purinergic receptor activation in microglia, and
these pathways are intimately involved in the expression and
release of inflammatory mediators including inducible nitric
oxide synthase (iNOS) and numerous cytokines and chemokines.
Because ischemic brain injury and oxygen reperfusion is a strong stimulus
of both microglial cell activation and neuronal damage/death, we have
developed an in vitro model system in which we can dissect the molecular
effects of adenine nucleotides on microglia that have been exposed to
and activated by hypoxia and reperfusion injury (HRI). The results of
these studies so far, indicate that there are at least 2 primary purinergic
receptors that mediate the responses to ATP in microglia, although they
do so utilizing different molecular mechanisms. In addition, exposure
to hypoxia alters the way microglia respond to ATP with regard to MAP
kinase pathway activation and inflammatory mediator production. Hence,
the goals of our research focus on delineating the role of the MAP kinase
pathways in controlling microglial cell production of inflammatory mediators,
and how hypoxia and HRI modulate the activity of P2 receptors and their
signaling pathways. Selective alterations in the activity of purinergic
receptors may provide a novel therapeutic target that can be exploited
to minimize damage to the brain following ischemic injury.
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