Inflammation triggers production of dimethylsphingosine from oligodendrocytes.

Neuropathic pain is a chronic, refractory condition that arises after damage to the nervous system. We previously showed that an increased level of the endogenous metabolite N,N-dimethylsphingosine (DMS) in the central nervous system (CNS) is sufficient to induce neuropathic pain-like behavior in rats. However, several important questions remain. First, it has not yet been demonstrated that DMS is produced in humans and its value as a therapeutic target is therefore unknown. Second, the cell types within the CNS that produce DMS are currently unidentified. Here we provide evidence that DMS is present in human CNS tissue. We show that DMS levels increase in demyelinating lesions isolated from patients with multiple sclerosis, an autoimmune disease in which the majority of patients experience chronic pain. On the basis of these results, we hypothesized that oligodendrocytes may be a cellular source of DMS. We show that human oligodendrocytes produce DMS in culture and that the levels of DMS increase when oligodendrocytes are challenged with agents that damage white matter. These results suggest that damage to oligodendrocytes leads to increased DMS production which in turn drives inflammatory astrocyte responses involved in sensory neuron sensitization. Interruption of this pathway in patients may provide analgesia without the debilitating side effects that are commonly observed with other chronic pain therapies.

Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome.

Cholesterol is an essential component of cellular membranes that is required for normal lipid organization and cell signaling. While the mechanisms associated with maintaining cholesterol homeostasis in the plasma and peripheral tissues have been well studied, the role and regulation of cholesterol biosynthesis in normal brain function and development have proven much more challenging to investigate. Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis characterized by mutations of 7-dehydrocholesterol reductase (DHCR7) that impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol and lead to neurocognitive deficits, including cerebellar hypoplasia and austism behaviors. Here we have used a novel mass spectrometry-based imaging technique called cation-enhanced nanostructure-initiator mass spectrometry (NIMS) for the in situ detection of intact cholesterol molecules from biological tissues. We provide the first images of brain sterol localization in a mouse model for SLOS (Dhcr7(-/-)). In SLOS mice, there is a striking localization of both 7DHC and residual cholesterol in the abnormally developing cerebellum and brainstem. In contrast, the distribution of cholesterol in 1-day old healthy pups was diffuse throughout the cerebrum and comparable to that of adult mice. This study represents the first application of NIMS to localize perturbations in metabolism within pathological tissues and demonstrates that abnormal cholesterol biosynthesis may be particularly important for the development of these brain regions.