Divergent Effects of Ovarian Steroids on Neuronal Survival during Experimental Allergic Encephalitis in Lewis Rats

Abstract

Experimental allergic encephalitis, (EAE) a Th1-cell-dependent autoimmune disease of the central nervous system (CNS) used to study immune responses relevant to multiple sclerosis (MS) displays gender susceptibility. The underlying basis of the sexual dimorphism may reflect multiple factors including gender-specific hormones. To study the relationship between ovarian hormones and CNS inflammation, we induced EAE in susceptible female Lewis rats ovariectomized (OVX) 7 days earlier and implanted with blank capsules or capsules containing estradiol (E), progesterone (P), or both (EP). Rats were immunized with complete Freunds' adjuvant alone or combined with guinea pig myelin basic protein. Motor function was scored 0–5 on standard criteria (days 7–11 postimmunization). On day 11, the rats were euthanized and the lumbar spinal cord was analyzed for Nissl, neuron nuclear antigen, and DNA fragmentation with a TUNEL assay. Inflammation was judged qualitatively on a scale of 0–4. Our immunization protocol induced limited sensorimotor deficits 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 inflammation (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 markedly 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 EAE in comparison to other groups. Coadministration of E with P prevented the consequences of P, including neuronal apoptosis (behavioral score, 0.6 ± 0.6; inflammation, 1.4 ± 0.5). Our results suggest a potential and novel function of P that increases the vulnerability of neurons to apoptotic injury in EAE and may have pathophysiologic implications in the progression of disability in women with MS.