Divergent effects of ovarian steroids on neuronal survival during experimental allergic encephalitis in Lewis rats

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.