Adaptaquin Case Reaction

Similarly, an increase in the levels of lipid peroxidation was observed in Aβ-induced rat hippocampal cells, confirming previous reports [17]. Enzymatic antioxidants such as SOD, catalase, and GPX act as the cellular antioxidant defense mechanism against free radicals. Since NADPH is required for the regeneration of catalase from its inactive form, catalase activity might be decreased in Aβ induced toxicity due to reduced NADPH levels. In this study, we have reported that Honokiol treatment significantly increased the enzymatic antioxidant activities in APP-CHO cells. In addition, non-enzymatic antioxidants like GSH also exhibited beneficial neuroprotective effects against oxidative stress. GSH is an endogenous nonenzymatic antioxidant that prevents damage to cellular components caused by ROS such as free radicals and peroxides. GSH is oxidized to glutathione disulfide (GSSG) by ROS, thereby causing a reduction in the level of GSH. GR reduces GSSG to GSH via NADPH, which in turn is released by glucose-6-phosphate dehydrogenase [18]. Honokiol treatment upregulated the activity of these antioxidants in APP-CHO cells. In addition to oxidative stress, a strong association between insulin resistance and the development of AD has been demonstrated. Several studies have reported that insulin resistance (IR), an underlying characteristic of type 2 diabetes, is an important risk factor for AD

With all living organisms, a process known as cell respiration is integral in order to provide the body with an essential form of energy, adenosine triphosphate (ATP). Oxygen, although an essential part of this process, can form reactants from colliding with electrons associated with carrier molecules. (pb101.rcsb.org, 2017). Hydrogen peroxide is an integral product of this reaction but is known to impose negative effects on the body if high levels are introduced. Explicitly, this reaction is caused “If oxygen runs into (one of these) carrier molecules, the electron may be accidentally transferred to it. This converts oxygen into dangerous compounds such as superoxide radicals and hydrogen peroxide, which can attack the delicate sulphur atoms and metal ions in proteins.” (pdbh101.rcb.org, 2017). Research has suggested that the hydrogen peroxide can be converted into hydroxyl radicals, known to mutate DNA, which can potentially cause bodily harm due to DNA’s role in the synthesis of proteins. These radicals can cause detrimental effects on the human body, and studies have suggested a link to ageing. Due to the harmful effects of these H2o2, it is important that the body finds a way to dispose of hydrogen peroxide before concentrations are too great.

It functions as a strong uncoupling agent on liver cell mitochondria, and further alter cell metabolism by uncoupling oxidative phosphorylation and glycolysis. More specifically, Tamoxifen inhibits the activities of complex II+III (IC50 =15µM) and complex V (IC50 =8.1µM) [6] of the electron transport chain. The IC50 doses of tamoxifen in liver cell mitochondria agree with reported cytotoxic doses in MCF10A and the observed cytotoxic doses in this study, which further supports that the potential mechanism governing tamoxifen toxicity is due to its inhibition of this pathway.

HMGB1 is a prototypic damage-associated molecular pattern (DAMP) protein highly secreted by activated macrophages and monocytes as a cytokine mediator of inflammation. This DNA-binding nuclear protein is released both passively during cell death and actively following cytokine stimulation. It is also implicated in both infectious and sterile inflammatory disorders [32-36] affecting the central nervous system (CNS) such as in Parkinson's disease (PD) [37], multiple sclerosis (MS) [38,39], ischemic stroke [40], traumatic brain injury (TBI) [41] and Alzheimer’s disease - AD [42-44]. HMGB1 activates cells by differential engagement of several membrane receptors including advanced glycation end products (RAGE), toll-like receptor 2 (TLR2), and TLR4 which are primarily responsible for HMGB1 pro-inflammatory activity and BBB impairment [45,46]. Specific to the proposed work, several studies have clearly outlined the role of OS in the development of microvascular and cardiovascular complications of 2DM [47].

A newer model for toxin-induced Parkinsonism is based on the herbizide rotenone. Rotenone is the most potent member of the rotenoids, a family of natural cytotoxic compounds extracted from various parts of Leguminosa plants. Like MPTP, rotenone is highly lipophilic and brain distribution is heterogeneous paralleling regional differences in oxidative metabolism (Talpade, Greene et al. 2000). In mitochondria, rotenone impairs oxidative phosphorylation by inhibiting nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase activity through its binding to the PSST subunit of the multipolypeptide enzyme complex I of the electron transport chain (Schuler and Casida 2001). Aside from its action on mitochondrial respiration, rotenone also inhibits

Since it is already known that Parkinsons is a neurodegerative disorder but the etiology is uncertain as regards what exactly can contribute to its original progression the need for Parkinson induced models is critical. 6-Hyroxydopamine (6-OHDA) is a compound specifically designed to determine the molecular mechanisms of neuronal death. 6-OHDA is the most widely used neurotoxin for both in vivo and in vitro studies to model the common Parkinson trait of nigral degeneration. 6-OHDA is a synthetic hydroxylated analogue compound of the normal endogenous neurotransmitter dopamine. The very first biological effects of 6-OHDA were demonstrated by (Porter et al., 1963) and (Stone et al., 1963) however the compound was first isolated in 1959 by Senoh (Senoh and Witkop, 1959).

The progression of the researchers’ work, however, is forestalled by the negatives and impracticality it has. Though the findings of Sp3 and 2C are valuable in future inhibitor development, the inhibitor proposed by Tsai and her team is impractical. Any inhibitor would have to cross the blood brain barrier (BBB) to reach the brain and its neurons. The BBB is formed by an endothelium of capillary vessels so for a drug, “to reach the brain, a molecule has first to be absorbed from the blood into the endothelial cell, where it is then released into the brain” (Seelig et al, 1994). For the drug to cross the BBB in this conventional way, also known as transmembrane diffusion, it must be lipid-soluble and have low molecular weight of around 400-500

Besides the appearance of episodic focal inflammatory lesions, there is a more generalized and progressive disease process that results in slow axonal , neuronal degeneration and subsequent accumulation of neurologic disabilities. The pathogenesis of this neurodegenerative process is aurged to the mitochondrial dysfunction which could be a key contributing mechanism ( Su et al., 2013)

Neonatal hypoxia-ischemia (HI) is a major cause of mortality and morbidity in infants and children. The most important consequences of neonatal HI is epilepsy. Epilepsy is a common neurodegenerative disorder characterized by recurrent of unprovoked seizures due to hyperexcitability and hypersynchrony of neuronal activity. Recent studies uncovered important molecular and cellular aspects of HI brain injury that may provide therapeutic target for intervening in the epileptogenesis in the developing brain. In our experiment approaches, we administrate RAGE antagonist to protect brain tissue from the effect of HI induced and inhibit apoptotic pathway and downstream products, including IL-6. Most importantly, the specific interaction between S100B

Ren et al. studied the effects of dexmedetomidine on seven-day old Sprague Dawley rats with left brain HI [3]. Various times after brain hypoxic ischemia, Sprague Dawley rats were given intraperetoneal Dex and were evaluated 7, 28 and 43 days after the brain hypoxia-ischemia. Intaperetoneal Dexmedetomidine dereased the brain cell and tissue loss as well as neurological and cognitive dysfunction when records were examined from 28 days after brain HI. This result has proved that post treatment by Dex confers neuroprotection against hypoxia-ischemia brain injury in neonatal rats which was possible because of inhibition of inflammation in the ischemic brain tissues through the activation of α2-adrenergic

Although not labeled for use in patients under the age of 18 years, recently it has been introduced into the NICU setting for procedural use, as well as short-term sedation. There are no structured reviews on the efficacy and safety profile of dexmedetomidine; however, animal studies have documented its potential neuroprotective effects and minimal respiratory side effects. A study out of Berlin examined the neuroprotective features of dexmedetomidine in reducing the detrimental effects of oxygen toxicity. Following single doses of dexmedetomidine at various concentrations, six-day old rats in the treatment group were exposed to 80% fiO2 for 24 hrs. Hyperoxia-exposed rats receiving dexmedetomidine pretreatment with a 10 mcg/kg dose one time were found to have significantly reduced hyperoxia-induced neurodegeneration in various brain regions (p<0.001). Hyperoxia-exposed rates receiving dexmedetomidine pretreatment in single dosages of 5 mcg/kg and 10 mcg/kg had significantly decreased expression of IL-1beta protein expression than controls exposed to hyperoxia without pretreatment (p<0.01 and p<0.001, respectfully). Although these neuroprotective findings were found in hyperoxia-exposed rats, it was noted that the normoxia-exposed control group had significantly increased percentage of cells stained positive for DNA strand breakage when pretreated with one dose 10 mcg/kg dexmedetomidine (p<0.001), raising concerns for varying safety profiles in different

In GSH-abundant tissues such as the retina, the most common type of protein oxidation is glutathionylation, which often affects the cysteines on the active sites of proteins and renders proteins dysfunctional (Hoppe et al., 2004). High amounts of PSSG eventually lead to cell injury and death due to the inactivation of multiple important proteins and enzymes (Ghezzi, 2013; Pastore and Piemonte, 2012). Therefore, reversing PSSG is vital to prevent cell damage and death. Specifically, the glutaredoxin family (Grxs) catalyzes the reduction of protein-glutathione mixed disulfides (PSSG) and therefore functions as powerful protein thiol oxidation repair enzymes (Holmgren, 2000; Lillig et al., 2008; Shelton et al., 2005). In mammalian cells, Grxs exist in two subsets: Grx1 and Grx2. Grx1 is primarily localized to the cytoplasm but has been implicated in the nucleus and inner mitochondrial membrane. Concentrated in the mitochondria ten times more than Grx1, Grx2 primarily exerts its protective effects in the mitochondrial matrix but has been associated with the nucleus as well (Gladyshev et al., 2001; Lundberg et al., 2001). Grx1 and Grx2 have a significant Cys-X-X-Cys active site motif. The two cysteine residues act as redox sensors and allow for a monothiol mechanism using the N-terminal cysteine to reduce

GSH is playing an important role in protecting some brain cells from reactive oxygen species which mean that the deficient in G6PD could be a risk factor for some neurodegenerative diseases. On the other hand, in different brain region and different cell types the oxidative damage of these area could have associated with pathological factors such as increasing the neuronal nuclear diameter, increased vaculation and increased prevalence of chromatolytic neurons which could happen after losing Purkinje cells

Alzheimer’s disease (AD) is a debilitating illness of the nervous system, affecting millions of geriatric population worldwide. Numerous factors are involved in the disease etiology viz. tau phosphorylation, amyloid β protein (Aβ) accumulation, lipid dysregulation, oxidative stress and inflammation. Among all factors oxidative stress plays a central role in the pathogenesis of AD leading to neuronal dysfunction and cell death (1). Oxidative stress is caused due to the increased production of reactive oxygen species (ROS) which denatures biomolecules such as proteins, lipids and nucleic acids through pathological redox reactions(2). Increased oxidative stress also results in excessive lipid peroxidation, weakening the cell membranes, causing

FAO produces a molecule of acetyl CoA in each oxidation cycle and two after full completed cycles. The resulted acetyl CoA is the major requirement for producing the reduced NADP+ in which the generated acetyl CoA enters the TCA cycle and with the availability of oxaloacetate provides citrate that can be export to the cytoplasm. The citrate then enters two reactions to produce cytosolic NADPH (1,3,12). These reactions include the conversion of malate to pyruvate that is catalyzed by malic enzyme (ME1) and the oxidation of isocitrate to α-ketoglutarate by isocitrate dehydrogenase (IDH1) (1,3,12). The produced cytosolic NADPH from FAO acts to sustain the antioxidant system against oxidative stress and to promote cancer cell survival. For instance, during severe oxidative stress the accumulation of oxygen reactive species (ROS) leads to cell death, cytosolic NADPH counteracts ROS by maintaining the reduced form of glutathione (GSH) thereby promoting cancer cell survival (12). In addition, the produced cytosolic NADPH from FAO targets ROS-induced oxidative damage to prevent disrupting mitochondrial and glycolytic ATP production. For example, in a study using SF188 glioblastoma cells the inhibition of FAO by CPTI inhibitor etomoxir hindered NADPH production and resulted in significantly increased of superoxide level in etomoxir treated cells, ATP depletion, and eventually cell death (12). A