Case Report: Molecular Analyses of Cell-Cycle-Related Genes in Cortical Brain Tissue of a Patient with Rasmussen Encephalitis.

Rasmussen's encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.

Reduction of oxidative stress and inflammatory signaling in the commissural nucleus of the solitary tract (commNTS) and rostral ventrolateral medulla (RVLM) in treadmill trained rats.

Inflammation has been associated with cardiovascular diseases and the key point is the generation of reactive oxygen species (ROS). Exercise modulates medullary neurons involved in cardiovascular control. We investigated the effect of chronic exercise training (Tr) in treadmill running on gene expression (GE) of ROS and inflammation in commNTS and RVLM neurons. Male Wistar rats (N = 7/group) were submitted to training in a treadmill running (1 h/day, 5 days/wk/10 wks) or maintained sedentary (Sed). Superoxide dismutase (SOD), catalase (CAT), neuroglobin (Ngb), Cytoglobin (Ctb), NADPH oxidase (Nox), cicloxigenase-2 (Cox-2), and neuronal nitric oxide synthase (NOS1) gene expression were evaluated in commNTS and RVLM neurons by qPCR. In RVLM, Tr rats increased Ngb (1.285 ± 0.03 vs. 0.995 ± 0.06), Cygb (1.18 ± 0.02 vs.0.99 ± 0.06), SOD (1.426 ± 0.108 vs. 1.00 ± 0.08), CAT (1.34 ± 0.09 vs. 1.00 ± 0.08); and decreased Nox (0.55 ± 0.146 vs. 1.001 ± 0.08), Cox-2 (0.335 ± 0.05 vs. 1.245 ± 0.02), NOS1 (0.51 ± 0.08 vs. 1.08 ± 0.209) GE compared to Sed. In commNTS, Tr rats increased SOD (1.384 ± 0.13 vs. 0.897 ± 0.101), CAT GE (1.312 ± 0.126 vs. 0.891 ± 0.106) and decreased Cox-2 (0.052 ± 0.011 vs. 1.06 ± 0.207) and NOS1 (0.1550 ± 0.03559 vs. 1.122 ± 0.26) GE compared to Sed. Therefore, GE of proteins of the inflammatory process reduced while GE of antioxidant proteins increased in the commNTS and RVLM after training, suggesting a decrease in oxidative stress of downstream pathways mediated by nitric oxide.

TRPV1 Contributes to Cerebral Malaria Severity and Mortality by Regulating Brain Inflammation.

Transient receptor potential vanilloid 1 (TRPV1) is a Ca+2-permeable channel expressed on neuronal and nonneuronal cells, known as an oxidative stress sensor. It plays a protective role in bacterial infection, and recent findings indicate that this receptor modulates monocyte populations in mice with malaria; however, its role in cerebral malaria progression and outcome is unclear. By using TRPV1 wild-type (WT) and knockout (KO) mice, the importance of TRPV1 to this cerebral syndrome was investigated. Infection with Plasmodium berghei ANKA decreased TRPV1 expression in the brain. Mice lacking TRPV1 were protected against Plasmodium-induced mortality and morbidity, a response that was associated with less cerebral swelling, modulation of the brain expression of endothelial tight-junction markers (junctional adhesion molecule A and claudin-5), increased oxidative stress (via inhibition of catalase activity and increased levels of H2O2, nitrotyrosine, and carbonyl residues), and diminished production of cytokines. Plasmodium load was not significantly affected by TRPV1 ablation. Repeated subcutaneous administration of the selective TRPV1 antagonist SB366791 after malaria induction increased TRPV1 expression in the brain tissue and enhanced mouse survival. These data indicate that TRPV1 channels contribute to the development and outcome of cerebral malaria.

Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells.

Inflammation and iron accumulation are present in a variety of neurodegenerative diseases that include Alzheimer's disease and Parkinson's disease. The study of the putative association between inflammation and iron accumulation in central nervous system cells is relevant to understand the contribution of these processes to the progression of neuronal death. In this study, we analyzed the effects of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) and of lipopolysaccharide on total cell iron content and on the expression and abundance of the iron transporters divalent metal transporter 1 (DMT1) and Ferroportin 1 (FPN1) in neurons, astrocytes and microglia obtained from rat brain. Considering previous reports indicating that inflammatory stimuli induce the systemic synthesis of the master iron regulator hepcidin, we identified brain cells that produce hepcidin in response to inflammatory stimuli, as well as hepcidin-target cells. We found that inflammatory stimuli increased the expression of DMT1 in neurons, astrocytes, and microglia. Inflammatory stimuli also induced the expression of hepcidin in astrocytes and microglia, but not in neurons. Incubation with hepcidin decreased the expression of FPN1 in the three cell types. The net result of these changes was increased iron accumulation in neurons and microglia but not in astrocytes. The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin. This connection may potentially contribute to the progression of neurodegenerative diseases by enhancing iron-induced oxidative damage.

Nigral neurodegeneration triggered by striatal AdIL-1 administration can be exacerbated by systemic IL-1 expression.

Neuroinflammation has been proposed as an important component of Parkinson's Disease (PD) aetiology and/or progression. However, the inflammatory components and the mechanisms underlying their effects are only partially known. By injecting an adenovirus expressing IL-1 in the striatum, we provoked progressive neurodegeneration of dopaminergic cells in the substantia nigra, motor symptoms and microglial activation. All these effects were attenuated by an anti-inflammatory treatment. Interestingly, peripheral inflammatory stimuli exacerbated IL-1beta induced neurodegeneration and the central inflammatory reaction. These data provide evidence that central, chronic IL-1beta expression can trigger and systemic IL-1beta exacerbate nigral neurodegeneration and highlight the functional relevance of this cytokine in PD.

Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation.

Inflammation, and in particular microglia activation, is regarded as a constant component of brain pathology in Parkinson's disease (PD). Microglial activation has been found in the substantia nigra (SN), one of the main brain regions affected in PD, for many years after the initiation of the disease. Although many studies point towards a deleterious role of inflammation on PD, the functional role of many of its main components has not been clarified yet. For example, tumor necrosis factor-alpha (TNF-alpha), a key pro-inflammatory cytokine, has been shown to exert toxic or no effects on the viability of dopaminergic neurons. No study has evaluated the effects of the long-lasting TNF-alpha expression in the SN, an experimental set-up most probably resembling the clinical situation. The aim of this study was to investigate the effects of the chronic expression of TNF-alpha in the adult SN at different time points. Adenoviral expression of low TNF-alpha levels (17-19 pg/mg) lasted for 14 days in the SN and did not induce interleukin-1beta (IL-1beta) expression. Long-lasting TNF-alpha expression caused dopaminergic cell death from day 14, increasing at 21 and 28 days compared with control animals injected with adenovectors expressing beta-galactosidase. TNF-alpha overexpression elicited irreversible, unilateral akinesia starting at 14 days, but not earlier. These effects were accompanied by microglial activation to stage 4 and/or monocyte/macrophage recruitment from the periphery from day 7 post adenovector inoculations. Thus, we conclude that extended duration of the expression of TNF-alpha is necessary and sufficient for a univocal toxic effect of TNF-alpha on dopaminergic neurons and motor disabilities. This study provides an animal model to study early events that lead to TNF-alpha-mediated neuronal demise in the SN. In addition, the cellular components of the inflammation elicited by TNF-alpha and the lack of IL-1beta expression support the growing idea of a distinct cytokine network in the brain.

HLA class II involvement in HIV-associated Toxoplasmic encephalitis development.

UNLABELLED: A total of 220 individuals were included in this study, 112 HIV-seronegative healthy individuals and 108 HIV-1-infected patients involving: 18 AIDS patients with Toxoplasmic encephalitis (AIDS-TE), 49 AIDS patients without TE, and 41 asymptomatic patients, were genotyping for DR and DQ loci by molecular biology techniques. Fisher's Exact test was used for statistical analysis. HLA-DQB*0402 and DRB1*08 alleles were associated with a high risk to develop opportunistic infections with neurological involvement, mainly Toxoplasma encephalitis in relationship with subjects healthy (OR = 20.43; Pc = 7.0 x 10(-6) and OR = 11; Pc = 2.6 x 10(-4), respectively); in relationship with AIDS no TE (OR = 6.98; Pc = 0.028 and OR = 4.85; P = 0.012, Pc = 0.14) and with patients in asymptomatic stage (OR = 61.50, Pc = 8.4 x 10(-6) and OR = 19.38; Pc = 3.9 x 10(-4)), respectively. CONCLUSIONS: It was concluded that the presence of HLA-DQB*0402 and DRB1*08 alleles in HIV-1-positive patients could be considered risk factors for developing neurological opportunistic infections, mainly Toxoplasmic encephalitis.