IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Progesterone effects in neuroinflammation and neurodegeneration
Autor/es:
DE NICOLA A.F.
Lugar:
Torino
Reunión:
Congreso; 7th International meeting Steroids and Nervous System; 2013
Institución organizadora:
Fondazione Cavalieri Ottolenghi
Resumen:
Far beyond its role in reproduction,
progesterone exerts neuroprotective, promyelinating and antiinflammatory
effects in the nervous system [1]. These effects are maximized under
pathological conditions, implying that changes of the local environment
sensitize the nervous tissues to steroid treatment [2]. In this presentation,
we will discuss our results of progesterone neuroprotection in a motoneuron
neurodegeneration model and a neuroinflammation
model. In the Wobbler mouse, a mutation of the Vsp54 gene leads to motoneuron
degeneration, astrogliosis and motor impairment. Motoneurons in the cervical spinal
cord of Wobblers show cytoplasmic vacuolation, decreased immunoreactivity for
choline-acetyltransferase (ChaT), decreased expression for Na,K-ATPase and
brain-derived neurotrophic factor (BDNF) mRNAs, decreased axonal transport and increased
activity of nitric oxide synthase (NOS), without the typical signs of apoptosis
[3]. Additionally, Wobbler mitochondrial present membrane rupture, cristolysis,
increased intramitochondrial NOS and decreased activity of respiratory chain
complexes [3]. Clinically, Wobblers suffer several degrees of motor impairment.
Treatment with progesterone (20 mg implant) from 3 weeks to 2 months markedly
modifies spinal cord neuropathology. Thus, progesterone reverses the impaired
expression of BDNF, ChAT and Na,K-ATPase, prevents oxidative damage of
motoneurons and their vacuolar degeneration, attenuates mitochondrial morphological
abnormalities, decreases the activity of NOS and enhances respiratory chain enzyme
activities [3]. Long-term treatment with progesterone also increases muscle
strength, biceps weigth and survival. Altogether, these data show that
progesterone strongly protects Wobbler motoneurons from degeneration. To study
progesterone effects in a neuroinflammation model resembling multiple sclerosis
(MS), we induced experimental autoimmune encephalomyelitis (EAE) in C57Bl6 mice.
In EAE mice we have analyzed if progesterone effects in the inflamed
spinal cord involves the decreased transcription of local inflammatory
mediators and the increased transcription of myelin proteins and myelin
transcription factors. To this purpose, C57Bl/6 female mice divided into
controls, EAE and EAE receive progesterone (100 mg implant), 7 days before EAE
induction. This procedure produces pregnancy progesterone
levels for the mouse. Tissues
are collected on day 17 post-immunization [4]. Real time PCR technology has demonstrated
that progesterone blocks the EAE-induced increase of the proinflammatory
mediators tumor necrosis factor alpha (TNFa) and its receptor TNFR1, the microglial marker CD11b
and toll-like receptor 4 (TLR4) mRNAs, and increases the mRNA expression of PLP
and MBP, the myelin transcription factors NKx2.2 and Olig1 and enhances CC1+
oligodendrocyte density respect of untreated EAE mice. Immunocytochemistry has demonstrated
decreased Iba1+ microglial cells. Using doble immunofluorescence labelling and
confocal microcoscopy, we have shown that TNFa colocalized with glial-fibrillary acidic protein+
astrocytes and OX-42 + microglial cells. Progesterone treatment also attenuates
the clinical signs of EAE. Therefore, the decreased inflammatory glial reactivity
and increased myelination from EAE mice receiving progesterone, supports that
steroid neuroprotection involves the modulation of transcriptional events in
the spinal cord of EAE mice. It is hoped that experimental data provided by animal models of
neurodegeneration and neuroinflammation open the ground for testing the
usefulness of neuroactive steroids for the prognosis and treatment of human neurological
disorders [5].
Reference list
[1]
Schumacher M, Sitruk-Ware R, De Nicola AF.
Progesterone and progestins:
neuroprotection and myelin repair. Curr Opin Pharmacol. 2008;8 :740-746.
[2] De Nicola AF, Labombarda F,
Deniselle MC, Gonzalez SL, Garay L, Meyer M,
Gargiulo G, Guennoun R, Schumacher M. Progesterone
neuroprotection in traumatic
CNS injury and motoneuron degeneration. Front Neuroendocrinol. 2009
;30:173-187.
[3]
Gonzalez Deniselle MC, Carreras MC, Garay
L, Gargiulo-Monachelli G, Meyer M, Poderoso JJ, De Nicola AF. Progesterone
prevents mitochondrial dysfunction in the spinal cord of wobbler mice. J
Neurochem. 2012;122 :185-195.
[4]
Garay LI, González Deniselle MC, Brocca ME, Lima A, Roig P, De
Nicola AF.
Progesterone down-regulates spinal cord inflammatory mediators and
increases
myelination in experimental autoimmune
encephalomyelitis. Neuroscience 2012 (in press).
[5] Gargiulo Monachelli G, Meyer M, Rodríguez GE,
Garay LI, Sica RE, De Nicola AF,
González Deniselle MC. Endogenous progesterone is associated to amyotrophic
lateral sclerosis prognostic factors. Acta Neurol Scand. 2011;123 :60-67.