During the past decade, mechanisms involved in the immune surveillance of the central nervous system (CNS) have moved to the forefront of neuropathological research mainly because of the recognition that most neurological disorders involve activation and, possibly, dysregulation of microglia, the intrinsic macrophages of the CNS. Increasing evidence indicates that, in addition to their well-established phagocytic function, microglia may also participate in the regulation of non specific inflammation as well as adaptive immune responses. This article focuses on the signals regulating microglia innate immune functions, the role of microglia in antigen presentation, and their possible involvement in the development of CNS immunopathology.

Immune function of microglia

Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.

Inflammation in Alzheimer disease: driving force, bystander or beneficial response?

Brain ischemia and reperfusion: Molecular mechanisms of neuronal injury

Treatment of inflammatory diseases today is largely based on interrupting the synthesis or action of mediators that drive the host's response to injury. Non-steroidal anti-inflammatories, steroids and antihistamines, for instance, were developed on this basis. Although such small-molecule inhibitors have provided the main treatment for inflammatory arthropathies and asthma, they are not without their shortcomings. This review offers an alternative approach to the development of novel therapeutics based on the endogenous mediators and mechanisms that switch off acute inflammation and bring about its resolution. It is thought that this strategy will open up new avenues for the future management of inflammation-based diseases.

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Inflammatory resolution: new opportunities for drug discovery.

Thiazolidinediones(TDs)是一类新型的胰岛素抵抗治疗药物。动物及临床实验证实TDs通过激活核受体过氧化物酶体增殖物激活受体-γ(PPAR-γ)显著增加胰岛素敏感性，改善胰岛β-细胞功能，降低血糖和胰岛素水平，缓解高血压及脂代谢紊乱，对2型糖尿病大血管和微血管病变亦具有保护作用。临床使用耐受性好，低血糖发生率低。但其中的Troglitazone具有明显的肝脏毒性。

胰岛素增敏剂一Thiazolidinediones研究现状

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.

Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

The importance of peroxisomes in central nervous system (CNS) comes from the observation that in several peroxisomal disorders, such as Zellweger syndrome, Adrenoleukodystrophy, Rhizomelyc chondrodysplasia punctata etc, severe neurological impairments were observed. They have been involved in several physiological processes in brain, such as protection against reactive oxygen species (ROS), myelinogenesis and very long chain fatty acid metabolism.

Peroxisomes and PPARs in cultured neural cells.

Our previous studies have demonstrated that specific peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists play a fundamental role in oligodendrocyte progenitor (OP) differentiation, protecting them against oxidative and inflammatory damage. The antihypertensive drug Telmisartan (TLM) was shown to act as a PPAR-γ modulator. This study investigates the TLM effect on OP differentiation and validates its capability to restore damage in a pharmacological model of Niemann-Pick type C (NPC) disease through a PPAR-γ-mediated mechanism. For the first time in purified OPs, we demonstrate that TLM-induced PPAR-γ activation downregulates the type 1 angiotensin II receptor (AT1), the level of which naturally decreases during differentiation. Like other PPAR-γ agonists, we show that TLM promotes peroxisomal proliferation and promotes OP differentiation. Furthermore, TLM can offset the OP maturation arrest induced by a lysosomal cholesterol transport inhibitor (U18666A), which reproduces an NPC1-like phenotype. In the NPC1 model, TLM also reduces cholesterol accumulation within peroxisomal and lysosomal compartments and the contacts between lysosomes and peroxisomes, revealing that TLM can regulate intracellular cholesterol transport, crucial for myelin formation. Altogether, these data indicate a new potential use of TLM in hypomyelination pathologies such as NPC1, underlining the possible repositioning of the drug already used in other pathologies.

The Antihypertensive Drug Telmisartan Protects Oligodendrocytes from Cholesterol Accumulation and Promotes Differentiation by a PPAR-γ-Mediated Mechanism.

Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.

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Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study

Retina can receive incidental γ-ray exposure from various sources. For example, although radiation therapy is a crucial tool for managing head and neck tumors, patients may develop ocular complications as collateral damage from accidental irradiation. Recently, there has been concern that retinal irradiation during space flight may compromise mission goals and long-term quality of life after space travel. Previously, in our in vitro model, we proved that immature retinal cells are more vulnerable to γ-radiation than differentiated neurons. Here, we investigate if a low-dose pre-irradiation (0.025 Gy), known to have a protective effect in various contexts, can affect DNA damage and oxidative stress in cells exposed to a high dose of γ-rays (2 Gy). Our results reveal that pre-irradiation reduces 2 Gy effects in apoptotic cell number, H2AX phosphorylation and oxidative stress. These defensive effects are also evident in glial cells (reduction in GFAP and ED1 levels) and antioxidant enzymes (catalase and CuZnSOD). Overall, our results confirm that rat retinal cultures can be an exciting tool to study γ-irradiation toxic effects on retinal tissue and speculate that low irradiation may enhance the skill of retinal cells to reduce damage induced by higher doses.

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Antonietta Bernardo

Papers

Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

Peroxisomes and PPARs in cultured neural cells.

The Antihypertensive Drug Telmisartan Protects Oligodendrocytes from Cholesterol Accumulation and Promotes Differentiation by a PPAR-γ-Mediated Mechanism.

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study

Adaptive Response in Rat Retinal Cell Cultures Irradiated with γ-rays