Marcela P. Vizcaychipi

Neuroinflammation: the role and consequences.

Neuroinflammation is central to the common pathology of several acute and chronic brain diseases. This review examines the consequences of excessive and prolonged neuroinflammation, particularly its damaging effects on cellular and/or brain function, as well as its relevance to disease progression and possible interventions. The evidence gathered here indicates that neuroinflammation causes and accelerates long-term neurodegenerative disease, playing a central role in the very early development of chronic conditions including dementia. The wide scope and numerous complexities of neuroinflammation suggest that combinations of different preventative and therapeutic approaches may be efficacious.

The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction

IntroductionThe impact of pro-inflammatory cytokines on neuroinflammation and cognitive function after lipopolysaccharide (LPS) challenge remains elusive. Herein we provide evidence that there is a temporal correlation between high-mobility group box 1 (HMGB-1), microglial activation, and cognitive dysfunction. Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability.MethodsEndotoxemia was induced in wild-type and IL-1R-/- mice by intra peritoneal injection of E. Coli LPS (1 mg/kg). Markers of inflammation were assessed both peripherally and centrally, and correlated to behavioral outcome using trace fear conditioning.ResultsIncrease in plasma tumor necrosis factor-α (TNFα) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1β, IL-6 and HMGB-1 was more persistent, with detectable levels up to day three. A 15-fold increase in IL-6 and a 6.5-fold increase in IL-1β mRNA at 6 hours post intervention (P < 0.001 respectively) was found in the hippocampus. Reactive microgliosis was observed both at days one and three, and was associated with elevated HMGB-1 and impaired memory retention (P < 0.005). Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis and ameliorated cognitive dysfunction without affecting HMGB-1 levels. Similar results were observed in LPS-challenged mice lacking the IL-1 receptor to those seen in LPS-challenged wild type mice treated with IL-1Ra.ConclusionsThese data suggest that by blocking IL-1 signaling, the inflammatory cascade to LPS is attenuated, thereby reducing microglial activation and preventing the behavioral abnormality.

Cognitive decline following major surgery is associated with gliosis, β-amyloid accumulation, and τ phosphorylation in old mice

Objective:Elderly patients undergoing major surgery often develop cognitive dysfunction and the mechanism of this postoperative complication remains elusive. We sought to determine whether postoperative cognitive dysfunction in old mice is associated with the pathogenesis of Alzheimers disease. Design:Prospective, randomized study. Setting:University teaching hospital-based research laboratory. Subjects:One-hundred and twenty C57BL/6 14-mo-old male mice (weighing 30-40 g). Interventions:Mice received intraperitoneal injections of either vehicle or Celastrol (a potent anti-inflammatory compound) for 3 days before undergoing sham surgery or partial hepatectomy, on the surgery day, and for a further 4 days after surgery. Cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimers disease were assessed 1 day after surgery day 1, 3, or 7. Measurements and Main Results:Cognitive impairment following surgery was associated with the appearance of certain pathologic hallmarks of Alzheimers disease: microgliosis, astrogliosis, enhanced transcriptional and translational activity of &bgr;-amyloid precursor protein, &bgr;-amyloid production, and &tgr; protein hyperphosphorylation in the hippocampus. Surgery-induced changes in cognitive dysfunction were prevented by the administration of Celastrol as were changes in &bgr;-amyloid and &tgr; processing. Conclusions:These data suggest that surgery can provoke astrogliosis, &bgr;-amyloid accumulation, and &tgr; phosphorylation in old subjects, which is likely to be associated with the cognitive decline seen in postoperative cognitive dysfunction.

The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats.

Objective:Xenon provides neuroprotection in multiple animal models; however, little is known about the other noble gases. The aim of the current study was to compare xenon, argon, and helium neuroprotection in a neonatal asphyxia model in rats. Design:Randomized controlled trial. Setting:Laboratory. Subjects:Seven-day-old postnatal Sprague-Dawley rats. Interventions:Seventy percent argon, helium, xenon, or nitrogen balanced with oxygen after hypoxic–ischemic brain injury. Measurements and Main Results:Control animals undergoing moderate hypoxic–ischemia endured reduced neuronal survival at 7 days with impaired neurologic function at the juvenile age compared with naïve animals. Severe hypoxic–ischemic damage produced a large cerebral infarction in controls. After moderate hypoxic–ischemia, all three noble gases improved cell survival, brain structural integrity, and neurologic function on postnatal day 40 compared with nitrogen. Interestingly, argon improved cell survival to naïve levels, whereas xenon and helium did not. When tested against more severe hypoxic–ischemic injury only, argon and xenon reduced infarct volume. Furthermore, postinjury body weight in moderate insult was lower in the helium-treated group compared with the naïve, control, and other noble gas treatment groups, whereas in the severe injurious setting, it is lower in both control and helium-treated groups than other groups. In the nondirectly injured hemisphere, argon, helium, and xenon increased the expression of Bcl-2, whereas helium and xenon increased Bcl-xL. In addition, Bax expression was enhanced in the control and helium groups. Conclusions:These studies indicate that argon and xenon provide neuroprotection against both moderate and severe hypoxia–ischemic brain injury likely through prosurvival proteins synthesis.

Central nervous system inflammation in disease related conditions: Mechanistic prospects

Inflammation is part of the innate immune response following insults to the body. This inflammatory reaction can spread throughout the systemic circulation and also into the central nervous system (CNS). CNS involvement has been demonstrated following acute peripheral insults including sepsis, surgery, burns and organ injury. It has also been observed in chronic conditions including obesity, diabetes and rheumatoid arthritis. Inflammation within the CNS is part of the pathogenesis of neurodegenerative diseases, in particular Alzheimers disease, multiple sclerosis and Parkinsons disease. These diseases are prone to exacerbation as a result of increased inflammation within the CNS following peripheral insult. The effect of inflammation within the CNS can also be modulated by other factors including age and also oestrogen, although how pro-inflammatory cytokines within the CNS cause clinical changes remains to be elucidated. The mechanism underlying the passage of inflammation from the periphery into the CNS also remains unclear. Evidence has led to the suggestion of two main pathways: blood brain barrier (BBB) dependent and BBB independent. This uncertainty has led to an increasing body of work exploring the processes involved in both the passage of inflammation into, and the effect of cytokines on, the CNS.

Effect of noble gases on oxygen and glucose deprived injury in human tubular kidney cells

The noble gas xenon has been shown to be protective in preconditioning settings against renal ischemic injury. The aims of this study were to determine the protective effects of the other noble gases, helium, neon, argon, krypton and xenon, on human tubular kidney HK2 cells in vitro. Cultured human renal tubular cells (HK2) were exposed to noble gas preconditioning (75% noble gas; 20% O2; 5% CO2) for three hours or mock preconditioning. Twenty-four hours after gas exposure, cell injury was provoked with oxygen–glucose deprived (OGD) culture medium for three hours. Cell viability was assessed 24 h post-OGD by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Other cohorts of cultured cells were incubated in the absence of OGD in 75% noble gas, 20% O2 and 5% CO2 and cellular signals phospho-Akt (p-Akt), hypoxia-inducible factor-1α (HIF-1α) and Bcl-2 were assessed by Western blotting. OGD caused a reduction in cell viability to 0.382 ± 0.1 from 1.0 ± 0.15 at control (P < 0.01). Neon, argon and krypton showed no protection from injury (0.404 ± 0.03; 0.428 ± 0.02; 0.452 ± 0.02; P > 0.05). Helium by comparison significantly enhanced cell injury (0.191 ± 0.05; P < 0.01). Xenon alone exerted a protective effect (0.678 ± 0.07; P < 0.001). In the absence of OGD, helium was also detrimental (0.909 ± 0.07; P < 0.01). Xenon caused an increased expression of p-Akt, HIF-1α and Bcl-2, while the other noble gases did not modify protein expression. These results suggest that unlike other noble gases, preconditioning with the anesthetic noble gas xenon may have a role in protection against renal ischemic injury.

Pre-treatment with isoflurane ameliorates renal ischemic–reperfusion injury in mice

AIMS Perioperative renal dysfunction is associated with a high mortality. The aim of this study was to investigate whether isoflurane preconditioning provides a protection against renal ischemic-reperfusion injury and whether hypoxia inducible factor 1 α (HIF-1 α) is responsible for the protection afforded by isoflurane in mice. MAIN METHODS Adult male C57BL/6 mice received vehicle (PBS), scrambled siRNA or HIF-1 α siRNA via hydrodynamic injection through tail vein. Twenty-four hours after injection, they were exposed to 1.5% isoflurane in oxygen enriched air for 2h while controls without injection were exposed to oxygen enriched air. Twenty-four hours after gas exposure, mice were sacrificed and their kidney were harvested for western blot while other cohorts underwent renal ischemia-reperfusion injury induced by bilateral renal pedicle clamping for 25 min for renal histological or functional analysis 24h after reperfusion or by unilateral clamping for 40 min for survival rate analysis. KEY FINDINGS Survival rate and the expression of HIF-1 α and erythropoietin were significantly increased while apoptosis, renal tubule score, blood plasma creatinine and urea were decreased by isoflurane preconditioning. HIF-1 α siRNA but not scrambled siRNA injection abrogated the protective effect of isoflurane preconditioning. SIGNIFICANCE Our data suggested that isoflurane preconditioning provided a protection against renal ischemic-reperfusion injury which is very likely due to hypoxia inducible factor-1 α upregulation.

Xenon pretreatment may prevent early memory decline after isoflurane anesthesia and surgery in mice.

Postoperative cognitive decline (POCD) is a common complication following surgery, but its aetiology remains unclear. We hypothesized that xenon pretreatment prevents POCD by suppressing the systemic inflammatory response or through an associated protective signaling pathway involving heat shock protein 72 (Hsp72) and PI3-kinase. Twenty-four hours after establishing long-term memory using fear conditioning training, C57BL/6 adult male mice (n = 12/group) received one of the following treatments: 1) no treatment group (control); 2) 1.8% isoflurane anesthesia; 3) 70% xenon anesthesia; 4) 1.8% isoflurane anesthesia with surgery of the right hind leg tibia that was pinned and fractured; or 5) pretreatment with 70% xenon for 20 minutes followed immediately by 1.8% isoflurane anesthesia with the surgery described above. Assessments of hippocampal-dependent memory were performed on days 1 and 7 after treatment. Hsp72 and PI3-kinase in hippocampus, and plasma IL-1β, were measured using western blotting and ELISA respectively, from different cohorts on day 1 after surgery. Isoflurane induced memory deficit after surgery was attenuated by xenon pretreatment. Xenon pretreatment prevented the memory deficit typically seen on day 1 (P = 0.04) but not on day 7 (P = 0.69) after surgery under isoflurane anesthesia, when compared with animals that underwent surgery without pretreatment. Xenon pretreatment modulated the expression of Hsp72 (P = 0.054) but had no significant effect on PI3-kinase (P = 0.54), when compared to control. Xenon pretreatment also reduced the plasma level increase of IL-1β induced by surgery (P = 0.028). Our data indicated that surgery and/or Isoflurane induced memory deficit was attenuated by xenon pretreatment. This was associated with a reduction in the plasma level of IL-1β and an upregulation of Hsp72 in the hippocampus.

Statins: the role in the treatment and prevention of Alzheimer's neurodegeneration.

Alzheimers disease (AD) is a progressive neurodegenerative disease commonly seen in the elderly and is characterized by progressive cognitive and physical decline. Current understanding of AD pathogenesis revolves around amyloid-β peptide (Aβ), a product of the sequential proteolytic cleavage of the transmembrane amyloid-β protein precursor (AβPP) by β- and γ-secretase, enzymes found predominantly in the cholesterol rich micro domains of the cell membrane. Several risk factors for AD are associated with cholesterol metabolism, including dyslipidaemia, coronary artery and cerebrovascular disease. Statins are widely prescribed for their cholesterol lowering ability and show a favorable side effect profile overall. By competitive inhibition of hydroxymethyl co-enzyme A-reductase, statins reduce the production of cholesterol and isoprenoid intermediates including geranylgeranyl and farnesyl pyrophosphate. These isoprenoids modify recently translated proteins such as small GTPase molecules that are essential in numerous cell-signaling pathways, including vesicular trafficking and inflammation. In experimental models of AD, statins reduce the production of Aβ by disrupting secretase enzyme function and by reducing neuroinflammation. Furthermore, epidemiological studies suggest that statins may reduce the incidence of AD. Consequently, statins, secondary of their anti-hypercholesterolaemic, plieotropic and anti-inflammatory effects, are being investigated for a potential therapeutic role. This review will discuss evidence for the role of statins in the treatment and prevention of AD neurodegeneration.

Heat Shock Protein 72 Overexpression Prevents Early Postoperative Memory Decline after Orthopedic Surgery under General Anesthesia in Mice

Background:Problems with learning and memory are common after surgery in the elderly and are associated with high morbidity. Heat shock protein 72 (Hsp72) confers neuroprotection against acute neurologic injury. We hypothesized that overexpression of Hsp72 would prevent the development of postoperative memory loss. Methods:C57BL/6 wild-type and Hsp72 overexpressing transgenic mice were randomly allocated to the following: control, isoflurane anesthesia alone, or tibial fracture during isoflurane anesthesia. Animals were trained 24 h before surgery using a fear conditioning protocol and assessed in their training environment and in a novel context on posttreatment days 1, 3, and 7. Microglial activation was assessed by immunostaining. Results:Adult male C57BL/6 wild-type mice exhibited reduced memory evidenced by a decreased percentage freezing time on days 1 and 3 after anesthesia alone (58.8 ± 5, 46.5 ± 5 mean ± SEM) and after surgery (53.4 ± 6, 44.1 ± 7), compared with controls (78.8 ± 5, 63.4 ± 6; P < 0.05 and P < 0.001, respectively). Hsp72 mice showed no difference by treatment on any day. Similarly, nonhippocampal-dependent memory was significantly impaired on days 1 and 3 after surgery and day 3 after anesthesia. The genotype effect was significant on days 1 and 7. CD68-immunopositive activated microglia in the hippocampus varied modestly with subregion and time; on day 7, there was a significant treatment effect with no genotype effect, with more activated microglia after surgery in all regions. Conclusion:Hsp72 overexpression is associated with prevention of postoperative hippocampal-dependent and -independent memory deficit induced by anesthesia and/or surgery. Memory deficit is not correlated with numbers of activated hippocampal microglia.