Acute Neuronal Apoptosis in a Rat Model of Multiple Sclerosis

Abstract

Demyelination caused by inflammation of the CNS has been considered to be a major hallmark of multiple sclerosis (MS). Using experimental autoimmune encephalomyelitis, a model of MS, we demonstrate that an immune-mediated attack of the optic nerve is accompanied by an early degeneration of retinal ganglion cells (RGCs). The decrease of neuronal cell density was correlated with functional disabilities as assessed by visual evoked cortical potentials and electroretinogram. Visual acuity was significantly reduced. DNA degradation and activation of caspase-3 in RGCs indicate that cell death of RGCs is apoptotic. These findings show for the first time that an inflammatory attack against myelin components can lead to acute neuronal cell loss by apoptosis.

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

“…46 Recently, we reported a loss of 65% of RGCs and a severe impairment of visual function occurring in early stages of MOG-EAE. 22 In our present study, Epo treatment promoted the survival of about 50% of these neurons that underwent apoptosis in vehicletreated controls in our neuro-inflammatory animal model. Moreover, an improvement in pattern ERG recordings at day 7 after immunization as well as at day 1 of MOG-EAE was detectable in Epo-treated animals, indicating that those RGCs rescued from apoptotic neuronal cell death had preserved their electrophysiological functions.…”

“…We have recently shown that healthy sham-immunized rats have visual acuity values of 1.3170.16 cycles per degree. 22 At the clinical onset of MOG-EAE, we observed a severe decline of specific cortical potentials in response to pattern stimulation in this previous study. In our present study, at day 7 after immunization the mean of discernable alternating bars with detectable VEP responses was located within the range of 6-12 bars (n ¼ 8 for each group) in the vehicle-treated as well as in the Epo-treated group.…”

“…Figure 2a). 22 In the vehicletreated EAE group, we observed 1262774 RGCs per square millimeter (n ¼ 8) at day 1 of MOG-EAE, corresponding to a survival of 46% of RGCs when compared to healthy controls. In contrast, RGC counts were significantly increased to 1917799 RGCs per square millimeter (n ¼ 8; Po0.05; Figure 2a and b) at day 1 of the disease in the Epo-treated group of rats.…”

“…55 The rats were injected intradermally at the base of the tail with a total volume of 200 ml inoculum, containing 50 mg rrMOG Igd in saline emulsified (1 : 1) with CFA (Sigma, St Louis, USA) containing 200 mg heat-inactivated Mycobacterium tuberculosis (strain H 37 RA from Difco Laboratories, Detroit, USA). 22 Rats were scored daily for clinical signs of EAE: grade 1, tail weakness or tail paralysis; grade 2, hindleg paraparesis or hemiparesis; grade 3, hindleg paralysis or hemiparalysis; grade 4, complete paralysis (tetraplegy), moribund state, or death. Statistical significance of the manifestation of the disease and the clinical score at day 8 of MOG-EAE were assessed using Student's t-test.…”

“…Recordings of VEPs and ERGs were performed as described previously. 22 Visual stimuli were presented on a 17-in monitor (Acer View 76i) positioned 20 cm in front of the eye. Light flashes of 20 ms duration were used at a rate of 1 Hz, and bar stimulation consisted of vertical gratings of variable spatial frequency, alternating in phase with a temporal frequency of 1.8 Hz at 66% Michelson contrast (constant mean luminance 15 cd/m 2 ).…”