Cortisol is neuroprotective and blocks microglial activation

[parkins1]

1: Brain Res Bull. 2000 Jul 15;52(5):391-6.

Inhibition of microglial cell activation by cortisol.

Drew PD, Chavis JA.

Department of Anatomy, University of Arkansas for Medical Sciences, Little Rock,
AR 72205, USA. drewpauld@exchange.uams.edu

Cortisol is a steroid hormone produced in response to stress. This glucocorticoid
can be toxic to neurons, and thus may be important in neurodegenerative diseases
including Alzheimer's disease. Activated microglia produce molecules including
nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) which can also be
toxic to neurons. The current study was designed to determine the effect of
cortisol upon the activation of primary cultured microglia and transformed N9
microglial cells. The studies indicate that cortisol represses lipopolysaccharide
(LPS) induction of nitric oxide production in these microglial cells. The hormone
acts by inhibiting the production of inducible nitric oxide synthase (iNOS) which
catalyses the synthesis of NO. Cortisol likely acts by blocking transcription of
iNOS gene expression since the hormone represses LPS induction of iNOS RNA levels
in these cells. Activated microglia produce increased TNF-alpha, in addition to
increased NO. The current studies demonstrate that cortisol inhibits release of
TNF-alpha from LPS-treated microglial cells. Collectively, these data suggest
that although cortisol may be directly toxic to neurons, the hormone may
indirectly protect neurons by blocking the production of cytotoxic molecules by
microglia.

PMID: 10922518 [PubMed - indexed for MEDLINE]

[parkins1]

1: Brain Res Brain Res Rev. 2005 Apr;48(2):302-21.

Glucocorticoid receptor-nitric oxide crosstalk and vulnerability to experimental
parkinsonism: pivotal role for glia-neuron interactions.

Marchetti B, Serra PA, Tirolo C, L'episcopo F, Caniglia S, Gennuso F, Testa N,
Miele E, Desole S, Barden N, Morale MC.

Neuropharmacology Section, OASI Institute for Research and Care on Mental
Retardation and Brain Aging (IRCCS), Troina (EN) Italy.
bianca.marchetti@oasi.en.it

Inflammation and oxidative stress have been closely associated with the
pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD).
The expression of inducible nitric oxide synthase (iNOS) in astrocytes and
microglia and the production of large amounts of nitric oxide (NO) are thought
to contribute to dopaminergic neuron demise. Increasing evidence, however,
indicates that activated astroglial cells play key roles in neuroprotection and
can promote recovery of CNS functions. Endogenous glucocorticoids (GCs) via
glucocorticoid receptors (GRs) exert potent anti-inflammatory and
immunosuppressive effects and are key players in protecting the brain against
stimulation of innate immunity. Here we review our work showing that exposure to
a dysfunctional GR from early embryonic life in transgenic (Tg) mice expressing
GR antisense RNA represents a key vulnerability factor in the response of
nigrostriatal dopaminergic neurons to the neurotoxin,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and further report that
exacerbation of dopaminergic neurotoxicity with no recovery is determined by
failure of astroglia to exert neuroprotective effects. Aberrant iNOS gene
expression and increased glia vulnerability to cell death characterized the
response of GR-deficient mice to stimulation of innate immunity. More
importantly, GR-deficient glial cells failed to protect fetal dopaminergic
neurons against oxidative stress-induces cell death, whereas wild-type glia
afforded neuroprotection. Thus, lack of iNOS/NO regulation by GCs can program an
aberrant GR-NO crosstalk in turn responsible for loss of astroglia
neuroprotective function in response to stimulation of innate immunity, pointing
to glia and efficient GR-NO dialogue as pivotal factors orchestrating
neuroprotection in experimental parkinsonism.

PMID: 15850669 [PubMed - indexed for MEDLINE]