Ge. Hoffman et al., Divergent effects of ovarian steroids on neuronal survival during experimental allergic encephalitis in Lewis rats, EXP NEUROL, 171(2), 2001, pp. 272-284
Experimental allergic encephalitis, (EAE) a Th1-cell-dependent autoimmune d
isease of the central nervous system (CNS) used to study immune responses r
elevant to multiple sclerosis (MS) displays gender susceptibility. The unde
rlying basis of the sexual dimorphism may reflect multiple factors includin
g gender-specific hormones. To study the relationship between ovarian hormo
nes and CNS inflammation, we induced EAE in susceptible female Lewis rats o
variectomized (OVX) 7 days earlier and implanted with blank capsules or cap
sules containing estradiol (E), progesterone (P), or both (EP). Rats were i
mmunized with complete Freunds' adjuvant alone or combined with guinea pig
myelin basic protein. Motor function was scored 0-5 on standard criteria (d
ays 7-11 postimmunization). On day 11, the rats were euthanized and the lum
bar spinal cord was analyzed for Nissl, neuron nuclear antigen, and DNA fra
gmentation with a TUNEL assay. Inflammation was judged qualitatively on a s
cale of 0-4. Our immunization protocol induced limited sensorimotor deficit
s in OVX rats (2.3 +/- 0.6, mean +/- SEM) with moderate inflammation (2.5 /- 0.4). E limited both behavioral impairments (1.0 +/- 0.4) and inflammati
on (0.5 +/- 0.2). P-treated rats had more severe sensorimotor deficits (3.1
+/- 0.5) with increased inflammatory infiltrates (3.6 +/- 0.4) and markedl
y increased numbers of TUNEL+ neurons. Neuron counts of the outer two Rexed
lamina (L3-L5) showed a 20% neuron loss (P < 0.02) in P-treated rats with
EA in comparison to other groups. Coadministration of E with P prevented th
e consequences of P, including neuronal apoptosis (behavioral score, 0.6 +/
- 0.6; inflammation, 1.4 +/- 0.5). Our results suggest a potential and nove
l function of P that increases the vulnerability of neurons to apoptotic in
jury in EAE and may have pathophysiologic implications in the progression o
f disability in women with MS. (C) 2001 Academic Press.