Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system and represents the most common neurological disorder in young adults in the Western hemisphere. There are several well-characterized experimental animal models that allow studying potential mechanisms of MS pathology. While experimental allergic encephalomyelitis is one of the most frequently used models to investigate MS pathology and therapeutic interventions, the cuprizone model reflects a toxic experimental model. Cuprizone-induced demyelination in animals is accepted for studying MS-related lesions and is characterized by degeneration of oligodendrocytes rather than by a direct attack on the myelin sheet. The present article reviews recent data concerning the cuprizone model and its relevance for MS. Particular focus is given to the concordance and difference between human MS patterns (types I-IV lesions) and cuprizone-induced histopathology, including a detailed description of the sensitive brain regions extending the observations to different white and grey matter structures. Similarities between pattern III lesions and cuprizone-induced demyelination and dissimilarities, such as inflamed blood vessels or the presence of CD3+ T cells, are outlined. We also aim to distinguish acute and chronic demyelination under cuprizone including processes such as spontaneous remyelination during acute demyelination. Finally, we point at strain and gender differences in this animal model and highlight the contribution of some growth factors and cytokines during and after cuprizone intoxication, including LIF, IGF-1, and PDGFalpha.
Microglia cells are the primary mediators of the CNS immune defense system and crucial for the outcome of shaping inflammatory responses. They are highly dynamic, moving constantly, and become activated by neuronal signaling under pathological conditions. They fulfill a dual role by not only regulating local neuroinflammation but also conferring neuronal protection. Gonadal steroids are known to exert anti-inflammatory effects in the CNS. Recently, we have shown that the microglial-like cell line BV-2 is hypoxia-sensitive and regulated by gonadal steroids. The present study used primary rat cerebral cortex-derived microglia to analyze whether this cell type directly perceive and respond to acute hypoxia. Second, we investigated whether 17β-estradiol (E2) and progesterone (P) interfere with hypoxia-induced changes. Short-term hypoxia increased the expression of a subset of pro-inflammatory (TNFa, IL1b) and oxidative stress-related (Hif1a) genes. The induction of TNFa and IL1b was counteracted by P. Hypoxia shifted the primary microglia to the pro-inflammatory M1 phenotype. The administration of E2 and P favored the neuroprotective M2 phenotype. Our findings extend previous data obtained with BV-2 cells and show that the primary microglia directly perceive hypoxia which increase their inflammatory activity. Both steroid hormones directly and indirectly interact with the microglia cells by reducing the inflammatory scenario and stimulating neuroprotection.
Demyelination of the cerebellum is a well-known phenomenon in human multiple sclerosis (MS). Concordantly, patients with MS frequently developed symptoms deriving from cerebellar lesions, i.e., dysmetria leading to hand dexterity impairment. Important advances in MS research have been made as a direct or indirect consequence of the establishment of adequate animal models. In this study, we used the cuprizone mouse model to investigate cerebellar demyelination in young adult male mice. The myelin status was analyzed by immunohistochemistry for proteolipoprotein and electron microscopy. The expression and presence of oligodendrocyte, astroglial, and microglia markers were supplementary studied. Cuprizone intoxication induced an almost complete demyelination of cerebellar nuclei. Cerebellar cortex regions were not (cortical gray matter) or only marginally (cortical white matter) affected. In addition, the affected areas displayed hypertrophic and hyperplastic astrocytosis accompanied by microglia or macrophage invasion. We conclude that cuprizone-induced demyelination pictures cerebellar deep gray matter involvement but not cerebellar cortex pathology as described for human MS. Behavioral changes after cuprizone described for this animal model may not only result from effects on commissural fiber tracts but also can arise from cerebellar demyelination.
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