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Biomedical subjects

Colm Cunningham

Publications and source records attributed to Colm Cunningham.

10 recordsLinked to original sources
PubMed2007

Systemic infections and inflammation affect chronic neurodegeneration.

It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.

Aging↗
PubMed2006

TGFbeta1 regulates the inflammatory response during chronic neurodegeneration.

The ME7 model of murine prion disease shows an atypical inflammatory response characterized by morphologically activated microglia and an anti-inflammatory cytokine profile with a marked expression of TGFbeta1. The investigation of the role of TGFbeta1 during a time course disease shows that its expression is correlated with (i) the onset of behavioral abnormalities, (ii) increased activated microglia, (iii) thickening of the basement membrane, and (iv) is associated with increased PrP(sc) deposition. Increasing TGFbeta1 using an adenoviral vector has no significant impact on prion-associated behavioral impairments or on neuropathology. In contrast, inhibition of TGFbeta1 activity using an adenovirus expressing decorin induces severe cerebral inflammation, expression of inducible nitric oxide synthase and acute neuronal death in prion-diseased animals only. These data suggest that TGFbeta1 plays a critical role in the downregulation of microglial responses minimizing brain inflammation and thus avoiding exacerbation of brain damage.

Animals↗
PubMed2005

Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration.

The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are "primed" to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1beta (IL-1beta) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1beta. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.

Animals↗
PubMed2005

Comparison of inflammatory and acute-phase responses in the brain and peripheral organs of the ME7 model of prion disease.

Chronic neurodegenerative diseases such as prion disease and Alzheimer's disease (AD) are reported to be associated with microglial activation and increased brain and serum cytokines and acute-phase proteins (APPs). Unlike AD, prion disease is also associated with a peripheral component in that the presumed causative agent, PrPSc, also accumulates in the spleen and other lymphoreticular organs. It is unclear whether the reported systemic acute-phase response represents a systemic inflammatory response to prion disease or merely reflects central nervous system (CNS) inflammation. For this study, we investigated whether intracerebrally initiated prion disease (ME7 model) provokes splenic, hepatic, or brain inflammatory and acute-phase responses. We detected no significant elevation of proinflammatory cytokines or activation of macrophages in the spleens of these animals, despite clear PrPSc deposition. Similarly, at 19 weeks we detected no significant elevation of transcripts for the APPs serum amyloid A, complement C3, pentraxin 3, and alpha2-antiplasmin in the liver, despite CNS neurodegeneration and splenic PrPSc deposition at this time. However, despite the low CNS expression levels of proinflammatory cytokines, there was robust expression of these APPs in degenerating brains. These findings suggest that PrPSc is not a stimulus for splenic macrophages and that neither peripheral PrPSc deposition nor CNS neurodegeneration is sufficient to produce a systemic acute-phase response. We also propose that serum cytokine and APP measurements are not useful during preclinical disease. Possible consequences of the clear chronic elevation of APPs in the CNS are discussed.

Acute-Phase Proteins↗
PubMed2003

Transforming growth factor-beta 1-mediated neuroprotection against excitotoxic injury in vivo.

Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1 beta and transforming growth factor beta 1 (TGF-beta 1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1 beta has been described as deleterious in acute injury, we decided to investigate the function of TGF-beta 1. An adenovirus expressing a constitutively active form of TGF-beta 1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-beta 1, the TGF-beta 1 adenovirus was replaced by recombinant human TGF-beta 1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-beta 1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-beta 1 cytokine.

Adenoviridae↗
PubMed2002

Atypical inflammation in the central nervous system in prion disease.

The inflammatory response in prion diseases is dominated by microglial activation. Contrary to their profile in vitro none of the pro-inflammatory cytokines interleukin-1beta, interleukin-6, or tumour necrosis factor-alpha are significantly upregulated in the ME7 model of prion disease. However, two major inflammatory mediators are elevated: transforming growth factor-beta1 and prostaglandin E2. This cytokine profile is the same as that reported for macrophages during phagocytosis of apoptotic cells and indeed transforming growth factor-beta1 and prostaglandin E2 are responsible for the downregulated phenotype of these macrophages. Transforming growth factor-beta1 may also have roles in extracellular matrix deposition and in amyloidogenesis and may play a direct role in disease pathogenesis. There is also now evidence to suggest that a peripheral infection, and its consequent systemic cytokine expression, may drive central nervous system cytokine expression and perhaps exacerbate disease.

Animals↗
PubMedDate not supplied

Managing pain in patients with dementia in hospital.

This is the fourth article in a series of five on dementia. Pain experienced by people with dementia is often poorly managed. Chronic pain can lead to further cognitive impairment, accidents and behavioural problems which can be minimised if the pain is properly assessed and managed. Patients with dementia receive fewer analgesics than any other patient group, but the likelihood of pain in this group is as high as in other older people. This article discusses the role of nurses in identifying and treating pain in patients with dementia. Approaches to assessment for improved detection and treatment of pain are outlined.

Acute Disease↗