Character Analysis Of VMAT2 LO Mice

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

Mitochondrial dysfunction and oxidative stress have been consistently observed in brains of PD patients. There is increasing pharmacological and genetic evidence sustain a link between PD and mitochondrial respiratory chain dysfunction, particular a deficit in mitochondrial complex I (Franco-Iborra et al., 2015). Accidental exposure to 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an mitochondrial complex I inhibitor, has been known to result in acute and irreversible syndrome that was almost indistinguishable from PD (Calne and Langston, 1983; Langston and Ballard, 1983). Later on, mitochondrial complex I inhibition has been identified in the brains of sporadic PD patients (Schapira et al., 1990). In addition, chronic systemic inhibition of mitochondrial complex I by pesticide rotenone has been found to link to sporadic PD (Betarbet et al., 2000). Interestingly, mitochondrial complex I deficiency has been found not only in the postmortem substantia nigra but also in cerebral cortex (Schapira et al., 1990), which is consistent to the cortical glucose hypometabolism observed in PD patients. Indeed, the pathology of PD has been found to involve several brain regions other than the SNc and many neurotransmitters other than dopamine (Lang and Obeso, 2004a, b). PD models using MPTP and rotenone have now been used extensively in PD research (Beal,

It has been well established that α- synuclein plays a role in the pathogenesis of PD (Spillantini MG et al., 1997; Wakabayashi et al 2007; Polymeropoulos MH et al., 1997; Singelton et al., 2003; Maries E et al., 2003). α-synuclein accumulates within the SN neurons, where it is trapped inside granules of pigments during the synthesis of neuromelanin much before there is evidence that neuromelanin is depleted in PD (Fasano M et al, 2003; Ikemura M et al, 2008; Michell AW et al., 2005). In PD, the peripheral nervous system (PNS) is also affected which is demonstrated by the fact that α-synuclein is also found in aggregates throughout the nervous system, including, enteric nervous system, sympathetic ganglia, submandibular gland, cardiac and pelvic plexuses, the skin and adrenal medulla (Shishido et al, 2010; Wakabayashi et al., 2010). It has been shown that α-synuclein immunoreactivity is increased in cutaneous peripheral nerves of PD when compared to those with other neurodegenerative disorders (Paisan Ruiz et al., 2009).

MPTP is a lipophilic compound that is able to cross the blood-brain barrier and convert into its fully oxidized metabolite, 1-methyl-4-phenylpyridinium ion (MPP+) (Monte, 2014). In this state, MPP+ has a higher affinity to bind dopamine transporters and be taken up by neurons. Beyond this, the mechanism for toxicity is unknown. However, it is hypothesized that MPP+’s ability to bind neuromelanin causes for the neuromelanin to act as a toxic reservoir. Nonetheless, it has been shown that neuromelanin concentration is decreased in those inflicted by Parkinson’s Disease

In spite of significant improvements in our knowledge of the pathogenesis of AD over recent decades, the precise mechanisms leading to AD development remain elusive. Over the years, several different hypotheses have been postulated to address the pathological lesions observed in AD. Indeed, oxidative stress has been consistently observed as an underlying biochemical anomaly in several neurodegenerative diseases including AD. However, whether oxidative stress presents a causal role or is secondary to AD pathogenesis remains unclear.[39] Markers for oxidative stress have been reported during early development of the disease and in patients with mild cognitive impairment well before the onset

Brain tissue analysis from human subjects displayed that all brains contained phosphorylated α-synuclein (monomers and oligomers) with obvious glial cytoplasmic inclusions in MSA subjects and neuron based inclusions for iLBD subjects like PD or Lewy body dementia (Bernis et al, 2015). Further examination of the phosphorylated α-synuclein species from the affected patients displayed detergent insolubility compared to normal controls (Bernis et al, 2015). No outward phenotypic expression of either MSA or iLBD were visible in the mice for the nine-month period post injection (Bernis et al, 2015). In the transgenic overexpression of human α-synuclein mouse group phosphorylated α-synuclein inclusion bodies were first observed within neurons at the six-month period following injection of cortical homogenates from both MSA and iLBD groups (Bernis et al, 2015). Inclusion bodies were observed primarily on the brain hemisphere associated with the injection site with a small amount of aggregation occurring on the opposite hemisphere (Bernis et al, 2015). Affected regions of the brain expanded to include the rostral and caudal regions of the brain and equal distribution in both brain hemispheres at the nine-month period (Bernis et al, 2015). Aggregates of phosphorylated α-synuclein were primarily housed within the soma of neurons however, a few aggregates were found in glial cells (astrocytes and microglia) (Bernis et al, 2015). Additional staining of

Though not clearly elucidated the development of Parkinson’s disease is proposed to be a confluence of both genetic and environmental factors (Medscape. 2015). Endogenous toxins have also been implicated (Mahan et al., 2012). One of the first evidential genetic causes for PD was the discovery of the polymorphism SNCA gene (Medscape. 2015). The SNCA gene encodes the protein called the alpha-synuclein, which is found on the neuronal

Perinatal asphyxia is a leading cause of mortality and morbidity in developing countries. During perinatal asphyxia, hypoxia leads to specific cellular changes affecting enzymatic activities, mitochondrial function, cytoskeletal structures, membrane transport and antioxidant defences. The mechanism of cellular injury in perinatal asphyxia is poorly understood, but is probably mediated by an excess concentration of neurotransmitters, and oxygen free radicals [1]. Perinatal asphyxia is shown to induce oxidative stress defined as a disturbance in the balance between antioxidants and pro-oxidants, with increased levels of pro-oxidants. Oxygen free radicals are extremely reactive chemical species that react with several living cell contents e.g.

A wide variety of dosing regimens are used to create the MPTP mouse model [155, 216-219]. In all cases, cell death is rapid with the first signs appearing within 12-72 hours and is maintained for several weeks [220]. Other hallmarks of PD observed include reductions in striatal DA and TH, elevated levels of acetylcholine, and reduced GSH [155, 221], as well as inflammatory markers and reactive gliosis [222, 223]. Mice administered MPTP display behavioral signs of decreased locomotor activity including akinesia and catalepsy [224]. The disadvantage of the MPTP model is that systemic MPTP lacks reproducibility in terms of behavioral changes and the degree of neurodegeneration. Many factors influence the reproducibility of the lesion, including

Peroxynitrite (ONOO−) is a well known potent oxidant and nitrating agent that is formed through the interaction of (NO•) with superoxide ion (O2•-) and its production is allied to the superoxide sources (for instance mitochondrial respiratory complexes or NAD(P)H oxidases present on plasma membrane) because superoxide is a shorter lived species and also shows constrained diffusion across biological membranes whereas NO• is quite stable and extremely diffusible free radical. In vivo, the rate of production in particular organelles (such as phagocytic vacuoles in macrophages) is very high as 50–100 μM per min. The ability of peroxynitrite to cross cell membranes despite of having short half-life at physiological pH (~10 ms) suggested that peroxynitrite formed could persuade adjoining target cells within one to two cell diameters (~5–20 μm) (Denicola et al., 1998). The decomposition of peroxynitrite occur via proton-catalyzed manner to form OH• and NO2• radicals in hydrophobic phases and initiates lipid peroxidation (Radi et al., 1991; Bartesaghi et al., 2006).

The part of oxidative stress in epilepsy is additionally bolstered by studies which suggest that

However, ROS production in mitochondria takes place under normal respiratory conditions but can be enhanced in response to various biotic and abiotic stress conditions. Complex I and III of mitochondrial electron transport chain are the sites of O2ˉ production. In aqueous solution, O2ˉ is moderately reactive, but this O2ˉ can further reduced by SOD dismutation to H2O2 (Quan et al., 2008)

It is possible that α-synuclein causes the ER stress by interrupting the vesicular protein trafficking and causing the ER to be overworked. It is also found that mutations in the parkin gene end up forming aggregations of its own substrates in the ER, which leads to stress and death of dopamine neurons (Imai et al., 2001). Other than the stress on the ER created by clusters of incorrectly folded α-synuclein proteins, mitochondria that are functioning improperly can also induce stress on the ER. Parkin is an E3 ubiquitin ligase responsible for regulating many cellular processes by tagging proteins with ubiquitin for their destruction (Dawson and Dawson 2010). A loss of function mutation in the parkin gene is seen to play a major role in altering the function of mitochondria leading to stress on the ER (Bouman et al., 2011). Mutations in PINK1 (PTEN induced putative kinase 1) affect pakin translocation and cause mitochondria to accumulate which increases the vulnerability of dopamine neurons (Song et al., 2013). Along with this, muations in both the parkin gene and PINK1 cause ER stress by increasing contacts between ER and dysfunctional mitochondrial, which can lead to neurodegeneration (Celardo et al., 2016). In rare forms of heredity Parkinson’s disease, mutations in

Prominent pathological facet of Parkinson’s Disease(PD) is the accumulation of intracytoplasmic lewy bodies caused by dominant mutations in ⍺-synuclein gene (SNCA). Recent studies suggest the role of toxic ⍺-synuclein oligomers in impairing several important cellular activities such as redox stability, mitochondrial functions, proteasomal and lysosomal degradation. Previous studies using a mouse model overexpressing A53T-SNCA by Mahalakshmi et al in Prof. Jochen Roeper’s lab, has found that under in-vivo conditions there is a Sustantia Nigra (SN) selective increase in action potential

Oligodendrocytes are the most vulnerable brain cells to oxidative stress due to its high metabolic demand for synthesizing myelin sheaths (Ichinose et al., 2014), and relatively low levels of antioxidants (Lassmann and Van Horssen, 2011). Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of MS. In the present study, cuprizone diet significantly increased brain TBARS level and decreased GSH content. These results are consistent with previous reports which reported that reactive oxygen species (ROS), produced as a consequence of alteration in the mitochondrial electron transport chain, have been implicated as mediators of demyelination and axonal damage in both MS and its animal models (Ghaiad et al., 2017; Kashani et al., 2014). On the other hand, treatment with linagliptin showed significant reduction in TBARS level and increase in GSH