Proinflammatory cytokine levels in the serum and cerebrospinal fluid of tuberculous meningitis patients

The pathophysiology underlying tuberculous meningitis (TBM), the most prominent extra pulmonary tuberculosis and a serious public health problem in developing countries is still unclear. Whereas, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are cytokines involved in cell-mediated immune response. TNF-alpha and IFN-gamma production has earlier been shown to be associated with tissue necrosis. To see whether these cytokines have any role to play in the pathophysiology of TBM, we measured the levels of serum and cerebrospinal fluid (CSF) TNF-alpha and IFN-gamma in 31 consecutive patients of TBM by ELISA. There was a remarkable rise (P<0.001) in the levels of serum and CSF TNF-alpha and IFN-gamma levels in TBM patients with respect to 20 age and sex-matched control subjects. Furthermore, TNF-alpha and IFN-gamma levels showed a positive correlation with the severity of the disease at the end of 6 months of antibiotic therapy. Elevated TNF-alpha and IFN-gamma levels, especially in CSF, despite of these patients undergoing multidrug therapy suggests the persistence of central nervous system inflammation. We also found an associated rise (P<0.001) in the nitric oxide (NO) levels of serum and CSF but there was no correlation between NO levels and the severity of TBM. The continuous release of cytokines despite these patients undergoing anti-tubercular therapy suggests that TBM severity may result mainly from the immune response rather than the organism itself.     

Both MHC and non-MHC genes regulate development of experimental neuropathic pain in rats

We have previously demonstrated that differences in neuropathic pain-like behaviors after sciatic nerve injury genetically maps to the major histocompatibility complex (MHC) in rats carrying RT1(c) or RT1(av1) haplotypes on the Piebald Virol Glaxo (PVG) background. In order to further explore the genetic contribution to neuropathic pain, we have here examined the MHC-congenic rat strains PVG-RT1(n) and PVG-RT1(av1) and the inbred strains PVG (RT1(c)) and Brown-Norway (BN; RT1(n)). All studied strains developed mechanical hypersensitivity (allodynia-like behavior) of the hind paw after photochemically induced sciatic nerve injury. However, the PVG-RT1(n) and PVG strains displayed significantly more allodynia than PVG-RT1(av1) and BN rats. In addition, the BN strain demonstrated an elevated threshold for the baseline response. The results demonstrate that both MHC and non-MHC genes influence experimental neuropathic pain in rats and also suggest that allelic variation contained in the RT1(av1) haplotype on the PVG background protects against neuropathic pain.     

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease

IntroductionFour less well-studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).MethodsCSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations.ResultsThe four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset.DiscussionEarly abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.     

Bone marrow-derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson's disease

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice results in dopamine neuron degeneration that is alleviated by prevention of microglia cell activation and blockade of iNOS production. However, the role of peripherally derived microglia in this response has not been well characterized. In the present study, we investigated the time course of infiltration and phenotypic differentiation of bone marrow-derived cells (BMDCs) following MPTP treatment in mice, using green fluorescent protein (GFP) bone marrow chimeras. BMDCs were found in the meninges, choroid plexus, blood vessels, and brain parenchyma in both saline and MPTP-treated mice. MPTP stimulated a transient, two-fold increase in the rate of BMDC infiltration into the brain, concomitant with the onset of microglia activation. The majority of BMDCs were microglial in phenotype, as assessed by morphology and expression of the pan-hematopoietic marker CD45 and the microglia marker CD11b. We did not observe BMDCs that expressed neuronal or astroglial markers. Over 90% of bone marrow-derived microglia expressed the inducible form of nitric oxide synthase (iNOS), suggesting that peripherally derived microglia may play a deleterious role in MPTP-induced degeneration.     

Einfluss des Schädel-Hirn-Traumas auf Zeitpunkt und Technik der Frakturversorgung

Zusammenfassung Das Schädel-Hirn-Trauma (SHT) ist bei Patienten <45 Jahren die häufigste Todesursache. Patienten mit schwerem SHT, die das initiale Trauma überleben, sind für sekundäre zerebrale Insulte besonders anfällig. Diese Sekundärschäden sind vorwiegend durch eine transiente Hypotension und/oder Hypoxämie in der frühen Behandlungsphase bedingt und beeinflussen entscheidend die Prognose nach schwerem SHT. Im Rahmen der direkten Traumafolge kommt es zu einer massiven endogenen Entzündungsreaktion im intrakraniellen Kompartment, die die Entwicklung des posttraumatischen Hirnödems und des verzögerten neuronalen Zelltodes zur Folge hat. Diese überschießende neuroinflammatorische Reaktion, deren eigentlicher phylogenetischer Sinn es ist, Schadenszonen abzugrenzen, nekrotisches Gewebe zu entfernen und eine Reparation der entstandenen Defekte zu vermitteln, bestimmt wesentlich das Ausmaß der sekundären Hirnschäden. Es ist deshalb bei Mehrfachverletzungen von entscheidender Bedeutung, diese pathophysiologischen Implikationen zu erkennen und einen iatrogenen, potentiell letalen, 2^nd hit für das verletzte Gehirn durch ein optimales Management zu vermeiden.Das bei isolierten Verletzungen übliche Konzept einer sofortigen, definitiven Frakturbehandlung muss bei mehrfachverletzten Patienten mit SHT durch ein modifiziertes Versorgungskonzept im Sinne einer orthopedic damage control mit temporärer externer Frakturfixation ersetzt werden. Hierbei werden biomechanische Gesichtspunkte der Frakturversorgung kompromisslos der Prioriät einer frühzeitigen intensivmedizinischen SHT-Therapie mit dem Ziel der Vermeidung sekundärer zerebraler Insulte untergeordnet.Die vorliegende Übersichtsarbeit soll den aktuellen Stand der pathophysiologischen Erkenntnisse der neuroinflammatorischen Kaskade nach SHT darstellen und aufzeigen, wie durch ein prioritätenorientiertes Behandlungskonzept der letalen Entität SHT adäquat Rechnung getragen wird.     

Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo

The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer’s disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (Aβ)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human Aβ1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1β, tumor necrosis factor- and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress Aβ-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.     

Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese

Manganese (Mn) can cause manganism, a neurological disorder similar to Parkinson’ Disease (PD). The neurobehavioral and neuroinflammatory end-points in the Mn post exposure period have not been studied yet. Rats were injected on alternate days with 8 doses of MnCl₂ (25 mg/kg) or saline, then euthanized 1, 10, 30 or 70 days following the last dose. Whole-blood (WB) (p < 0.05), urine (p < 0.05) and brain cortical (p < 0.0001) Mn levels were significantly increased 24 h after the last dose. Decreases in the rats’ ambulation were noted 1, 10 and 30 days after the last Mn dose (p < 0.001; p < 0.05; p < 0.001, respectively) and also in the rearing activity at the four time-points (p < 0.05). Cortical glial fibrillary acid protein immunoreactivity (GFAP-ir) was significantly increased at 1, 10, 30 (p < 0.0001) and 70 (p < 0.001) days after the last Mn dose, as well as tumor necrosis α (TNF-α) levels (p < 0.05) but just on day 1. Taken together, the results show that, during the 70-day clearance phase of Mn, the recovery is not immediate as behavioral alterations and neuroinflammation persist long after Mn is cleared from the cortical brain compartment.     

Protective effect of betulinic acid against intracerebroventricular streptozotocin induced cognitive impairment and neuronal damage in rats: Possible neurotransmitters and neuroinflammatory mechanism

Background

The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats.

MRI visualization of neuroinflammation using VCAM-1 targeted paramagnetic micelles

The detection of neuroinflammatory processes using innovative and non-invasive imaging techniques is of great help to deeply investigate the onset and progression of neurodegenerative diseases. Since Vascular Cell Adhesion Molecule (VCAM-1) is over expressed at the blood brain barrier in the event of neuroinflammation, the goal of this work was the testing of MRI detectable micelles targeted towards VCAM-1 to visualize inflamed regions in a mouse model of acute neuroinflammation. The developed probe allowed for the early detection of the disease, with higher T₁ signal enhancement and more precise localization in comparison to untargeted micelles or to the clinically approved contrast agent MultiHance. Moreover, the relatively long blood half-life of the nanosystem (ca. 6.3 h) guaranteed a good accumulation in the inflamed regions, paving the way to future diagnostic/theranostic applications, implying the loading of neuroprotective or even anti-cancer drugs inside the core of the micelles.     

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1beta, TNF-alpha and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1beta, TNF-alpha, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1beta was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-alpha was expressed to a lesser extent than IL-1beta, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrate the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.