Sex hormones, for example, estrogen and progesterone, are thought to affect and delay progression of multiple sclerosis (MS) in pregnant women. Although both steroid hormones are neuroprotective in the brain and elevated during pregnancy, only estrogen was tested in clinical trials. To evaluate the role of 17beta-estradiol (E) and progesterone (P) in prevention demyelination, young adult male mice were fed with cuprizone for a defined time interval and simultaneously treated with steroids by repeated injections into the neck region. The status of myelination was analyzed by magnetic resonance imaging and conventional histological staining. The individual application of E and P resulted only in a moderate prevention of demyelination in the corpus callosum (CC). The combined treatment with both steroid hormones counteracted the process of demyelination. Expression of the mature (PLP and MBP) and premature (PDGF-alpha-R) oligodendrocyte markers were significantly increased after hormone application in the affected CC. In addition, both hormones stimulated astrogliosis and the expression of IGF-1. Microglial invasion in demyelinated CC was pronounced and additionally localized in the midline of CC after hormone treatment. These data show that sex steroids can protect the brain from demyelination and stimulate remyelination. It appears that only the administration of both hormones is fully effective. The beneficial steroid effect requires interactions with oligodendrocytes possibly by preventing their degeneration or recruitment from precursor cells which are stimulated to remyelinated fibers. The positive hormonal influence on myelination in the CNS may be a future therapeutically strategy for the treatment of MS.

Memory impairment is outstanding within the spectrum of cognitive deficits in multiple sclerosis (MS) patients. Demyelination has been reported in the hippocampus formation of MS patients. The degree of hippocampus lesions in MS strongly correlates with progression of cognitive dysfunction. Because no appropriate animal model for the study of hippocampus demyelination has been established, we used the cuprizone mouse model to investigated demyelination in young adult and aged mice. The myelin status was analyzed by classical histological staining, immunocytochemistry for proteolipoprotein, and electron microscopy. Oligodendrocyte, astroglial, and microglia markers were studied. Cuprizone intoxication induced an almost complete demyelination of distinct hippocampus subregions to a similar extent in young adult and aged male mice. Demyelination was pronounced in a subset of white and gray matter areas, i.e., the stratum lacunosum moleculare containing the perforant path, medial alveus, stratum pyramidale in the cornu ammonis 2/3 region, and hilus region. Besides demyelination, affected areas displayed hypertrophic and hyperplastic astrocytosis. No significant effect on microglia invasion was detected at any investigated time point (0, 3, 5, and 7 weeks). We conclude that cuprizone-induced demyelination provides an adequate animal model to investigate appropriate therapy strategies for the prevention of hippocampus demyelination.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.

Astroglia is well-known to be integrated in the complex regulation of neuroinflammation in the central nervous system. Astrocytes become activated and synthesize cytokines, chemokines, and prostanoids during degenerative and vulnerable processes and interact with other immune-competent cells. Degenerative disorders often occur in a brain-region-specific fashion suggesting differences in the activity and reactivity of innate immune cells. We have investigated the potency of lipopolysaccharides (LPS) to differently stimulate astrocytes from the cortex and midbrain. Astroglial cultures were prepared from Bagg albino/c mice and exposed to LPS. Astrocytes from both brain areas already differed in their capacity and profile of cytokine expression under basal unstimulated conditions. In response to LPS, we observed both a region-specific pattern of up-regulation of distinct cytokines and differences in the extent and time-course of activation. Our data demonstrate that astrocytes reveal a region-specific basal profile of cytokine expression and a selective area-specific regulation of cytokines upon LPS-induced inflammation. This makes astrocytes likely candidates to be responsible for region-specific incidence rates of neurological and neurodegenerative disorders.

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