Annette Kirchgessner

Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies.

Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. In this review we discuss the role of matrix metalloproteinases (MMPs) in blood-brain barrier (BBB) disruption as a consequence of ischemic stroke. MMP-9 in particular appears to play an important role in tPA-associated hemorrhagic complications. Reactive oxygen species can enhance the effects of tPA on MMP activation through the loss of caveolin-1 (cav-1), a protein encoded in the cav-1 gene that serves as a critical determinant of BBB permeability. This review provides an overview of MMPs’ role in BBB breakdown during acute ischemic stroke. The possible role of MMPs in combination treatment of acute ischemic stroke is also examined.

Neuroinflammation in inflammatory bowel disease

Inflammatory bowel disease is a chronic intestinal inflammatory condition, the pathology of which is incompletely understood. Gut inflammation causes significant changes in neurally controlled gut functions including cramping, abdominal pain, fecal urgency, and explosive diarrhea. These symptoms are caused, at least in part, by prolonged hyperexcitability of enteric neurons that can occur following the resolution of colitis. Mast, enterochromaffin and other immune cells are increased in the colonic mucosa in inflammatory bowel disease and signal the presence of inflammation to the enteric nervous system. Inflammatory mediators include 5-hydroxytryptamine and cytokines, as well as reactive oxygen species and the production of oxidative stress. This review will discuss the effects of inflammation on enteric neural activity and potential therapeutic strategies that target neuroinflammation in the enteric nervous system.

Anti-inflammatory effects of nicotine in obesity and ulcerative colitis

Cigarette smoke is a major risk factor for a number of diseases including lung cancer and respiratory infections. Paradoxically, it also contains nicotine, an anti-inflammatory alkaloid. There is increasing evidence that smokers have a lower incidence of some inflammatory diseases, including ulcerative colitis, and the protective effect involves the activation of a cholinergic anti-inflammatory pathway that requires the α7 nicotinic acetylcholine receptor (α7nAChR) on immune cells. Obesity is characterized by chronic low-grade inflammation, which contributes to insulin resistance. Nicotine significantly improves glucose homeostasis and insulin sensitivity in genetically obese and diet-induced obese mice, which is associated with suppressed adipose tissue inflammation. Inflammation that results in disruption of the epithelial barrier is a hallmark of inflammatory bowel disease, and nicotine is protective in ulcerative colitis. This article summarizes current evidence for the anti-inflammatory effects of nicotine in obesity and ulcerative colitis. Selective agonists for the α7nAChR could represent a promising pharmacological strategy for the treatment of inflammation in obesity and ulcerative colitis. Nevertheless, we should keep in mind that the anti-inflammatory effects of nicotine could be mediated via the expression of several nAChRs on a particular target cell.

Gut inflammation in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood. Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorders pathogenesis.Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease. In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut.If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder. For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.

The emerging role of dietary fructose in obesity and cognitive decline.

The incidence of obesity has increased dramatically over the past several years, and in parallel, so has the prevalence of type 2 diabetes (T2D). Numerous studies have demonstrated that both obesity and T2D are associated with lower cognitive performance, cognitive decline, and dementia. Intake of dietary fructose has also increased. In fact, high-fructose corn syrup (HFCS) accounts for as much as 40% of caloric sweeteners used in the United States. Given the increase in the incidence of Alzheimer’s disease (AD), characterized by an age-related decline in memory and cognitive functioning, in this report we review the effects of obesity on cognitive performance and the impact of high fructose intake in promoting cognitive decline. The paper then considers the effects of omega-3 fatty acids (FAs), which have been linked to promising results in cognitive function including ameliorating the impact of a high-fructose diet.

Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction

Obesity is a chronic disease characterized by persistent low-grade inflammation with alterations in gut motility. Motor abnormalities suggest that obesity has effects on the enteric nervous system (ENS), which controls virtually all gut functions. Recent studies have revealed that the gut microbiota can affect obesity and increase inflammatory tone by modulating mucosal barrier function. Furthermore, the observation that inflammatory conditions influence the excitability of enteric neurons may add to the gut dysfunction in obesity. In this article, we discuss recent advances in understanding the role of gut microbiota and inflammation in the pathogenesis of obesity and obesity-related gastrointestinal dysfunction. The potential contribution of sirtuins in protecting or regulating the circuitry of the ENS under inflamed states is also considered.

Corrigendum: Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

[This corrects the article on p. 32 in vol. 4, PMID: 23565108.].