Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis.

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.

Increase in mRNA Level of Orexin1 and 2 Receptors Following Induction of Experimental Autoimmune Encephalomyelitis in Mice.

Orexin A and B are hypothalamic peptides with a wide variety of effects such as anti-inflammation and neuroprotection. Impaired function of orexin system has been reported in some neurodegenerative diseases like Parkinson, Huntington and Alzheimer. In this study, the mRNA expression levels of some hypothalamic peptides were investigated in C57BL/6 female mice with experimental autoimmune encephalomyelitis (EAE). Animals were randomly divided into two control and EAE groups. EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG) with complete Ferund's adjuvant and pertussis toxin. Twenty-first days following immunization, mice were decapitated to remove the brains. Then, the expression profiles of prepro-orexin, orexin 1 receptors (OX1R) and orexin 2 receptors (OX2R) in hypothalamic region were assessed using real-time PCR method. In this study, we found a considerable increase in the mRNA expression of OX1R and OX2R following EAE induction in C57BL/6 mice. Elevation levels of OX1R and OX2R following EAE induction suggest that alteration in orexinergic system may involve in pathogenesis of multiple sclerosis.

Susceptibility-weighted imaging in the experimental autoimmune encephalomyelitis model of multiple sclerosis indicates elevated deoxyhemoglobin, iron deposition and demyelination.

BACKGROUND: Susceptibility-weighted imaging (SWI) is an iron-sensitive magnetic resonance imaging (MRI) method that has shown iron-related lesions in multiple sclerosis (MS) patients. The contribution of deoxyhemoglobin to the signals seen in SWI has not been well characterized in MS. OBJECTIVES: To determine if SWI lesions (seen as focal hypointensities) exist in the experimental autoimmune encephalomyelitis (EAE) animal model of MS, and to determine whether the lesions relate to iron deposits, inflammation, demyelination, and/or deoxyhemoglobin in the vasculature. METHODS: We performed SWI on the lumbar spinal cord and cerebellum of EAE and control mice (both complete Freund's adjuvant/pertussis toxin (CFA/PTX)-immunized and naive). We also performed SWI on mice before and after perfusion (to remove blood from vessels). SWI lesions were counted and their locations were compared to histology for iron, myelin and inflammation. RESULTS: SWI lesions were found to exist in the EAE model. Many lesions seen by SWI were not present after perfusion, especially at the grey/white matter boundary of the lumbar spinal cord and in the cerebellum, indicating that these lesion signals were associated with deoxyhemoglobin present in the lumen of vessels. We also observed SWI lesions in the white matter of the lumbar spinal cord that corresponded to iron deposition, inflammation and demyelination. In the cerebellum, SWI lesions were present in white matter tracts, where we found histological evidence of inflammatory perivascular cuffs. CONCLUSIONS: SWI lesions exist in EAE mice. Many lesions seen in SWI were a result of deoxyhemoglobin in the blood, and so may indicate areas of hypoxia. A smaller number of SWI lesions coincided with parenchymal iron, demyelination, and/or inflammation.

Definition of arousal and mechanistic studies in intact and brain-damaged mice.

The existence of a primitive, elemental form of CNS arousal, "generalized arousal," has been hypothesized; it has been given an operational definition, and a high throughput assay has been assayed for it in mice. Many of the ascending and descending neuroanatomical pathways are fairly well understood. To begin experiments that might have potential implications for therapeutic measures, mice were rendered anoxic and it was shown that the assay can demonstrate behavioral abnormalities not detected with a standard neurological screen. These behavioral deficiencies are reminiscent of "sundowning," a form of dementia seen in hospitalized elderly patients. Electrical stimulation of neurons in medial thalamic cell groups can increase activity in the generalized arousal assay. Current studies include attempts to achieve temporal patterns of electrical stimulation that would take advantage of nonlinear properties of ascending arousal pathways.

Maternal deprivation and early weaning modulate experimental allergic encephalomyelitis in the rat.

The present experiment deals with the effect of maternal deprivation (MD) and early weaning (EW) on the development and course of experimental allergic encephalomyelitis (EAE) in Dark August (DA) rats. Five litters (five to nine pups per liter) were subjected to MD (4 h daily) from Day 1 until Day 28. EW rats were weaned on Day 15 (EW-15, five litters) or Day 21 (EW-21, four litters). Control rats and MD rats were weaned on Day 28. At the age of 8 weeks, rats were immunized with guinea pig spinal cord in complete Freund's adjuvant and clinical signs of EAE were recorded daily. On Day 18 after immunization, rats were bled and sacrificed. Brain and spinal cord were examined histologically for EAE lesions. Serum anti-rat myelin basic protein (MBP) antibodies were detected by ELISA. MD female rats exhibited suppression of neurological and histological signs of EAE in comparison with control rats. MD and control females showed elevated anti-MBP antibody level compared to MD and control males. EW-15 female rats demonstrated potentiation of neurological signs of EAE compared to control females. EW-21 females developed more severe clinical signs and histological lesions compared to control females. These results show that neonatal experiences, such as maternal deprivation and early weaning, influence the development of EAE in adult DA rats.