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  • AZD 0530 what br Neurodegenerative diseases definition and c

    2019-07-04


    Neurodegenerative diseases: definition and categories Diseases that their progression is dependent on the formation of protein aggregates, are generally identified as protein aggregation diseases. Most common among them is neurodegenerative diseases, in which the protein abnormally AZD 0530 what and deposits in particular parts of the neural network, interrupting its function. PD and AD are two well-established types of neurodegenerative diseases. Though, it has been found that several other similar disorders, besides those with lower incidence are also considered as neurodegenerative diseases (Kumar et al., 2016; Rasool et al., 2014). AD is one of the most predominant neurodegenerative diseases worldwide. AD is a debilitating neurodegenerative disease, associated with progressive memory deficits and cognitive impairments, which brings large economic and social burdens (Mattson, 2004). A key etiological factor of AD is known to be amyloid β (Aβ), derived from the amyloid precursor proteins. PD is the second most prevalent neurodegenerative disorder after AD and affects 3% of people over 75 years. The main symptoms of PD include bradykinesia, rigidity, tremor, postural and gait impairments (Massano and Bhatia, 2012). PD is a destruction of dopaminergic neurons in the substantia nigra and is characterized by reduced dopamine levels in the striatum. The exact causal of PD remains unclear; however, neuroinflammation is known to o be crucial in development of the disease (Amor et al., 2010; Renaud et al., 2015; Shahpiri et al., 2016). Currently, the term ‘neurodegeneration’ has AZD 0530 what been broadly accepted in multiple sclerosis (MS) pathogenesis; although, to some extent differs from the description of classical neurodegenerative diseases. Preclinical and clinical studies support the potential efficacy of a combinatory use of both anti-inflammatory and neuroprotective drugs to improve the therapy against MS (Milo and Panitch, 2011). A wide range of neurological evidence as well as positive responses to the anti-inflammatory agents support the fact that MS is a primary inflammatory disease (Stadelmann, 2011). Moreover, HD and amyotrophic lateral sclerosis (ALS) are two other types of neurodegenerative disorders (Rasool et al., 2014).
    Molecular and cellular pathology of neurodegeneration It has been evidenced that a variety of neuropathological hallmarks are implicated to neurodegenerative disorders including oxidative stress, degradation of neurotransmitters in the synaptic cleft mediated by over activity of related enzymes, aggregates of proteins in neurons, depletion or insufficient production of neurotransmitters, excitotoxicity of neurons mitochondrial dysfunction, abnormal ubiquitination, disturbances in blood brain barrier (BBB) function, and overexpression of pro-inflammatory cytokines and inflammatory reactions (Rasool et al., 2014; Wong and Cuervo, 2010). The neuroinflammatory cascade triggers when proliferation and stimulation of astrocytes and microglia are increased, also by overproduction of pro-inflammatory cytokines neuropeptides and chemokines. Upregulation and stimulation of pathogen-specific receptors—such as human Fc gamma receptors (FcγRs) and CD8⁺ αβ T-cell receptor (CD8⁺ TCRαβ) lead to overproduction of inflammatory parameters such as inflammatory cytokines like tumor necrosis factor (TNF)-α and interleukin (IL) −1, as well as chemokines; interleukin (IL)-8 (Holmes, 2013; McManus and Heneka, 2017). Activation of neuroinflammatory cytokines can interrupt the permeability of BBB and neurovascular endothelium, also enhance the infiltration of leukocytes and antibodies. Neuroinflammation potentially stimulates synaptic dysfunction and neuronal cells death through a mechanisms involving overproduction of pro-inflammatory cytokines and chemokine. For instance, it has been reported that overexpression of IL-1, IL-6, and TNF-α, as well as activation of cyclooxygenase (COX-2) enzyme in the endothelium disturb the integrity of the BBB and results in transmission of the neutrophils into the CNS (McManus and Heneka, 2017). High or chronic oxidative stress is believed to be a principal factor in development of neurodegeneration pathogenesis. Hydrogen peroxide (H2O2), one of the main reactive oxygen species (ROS) involved in oxidative damage via the Fenton reaction, can cause apoptosis of neural cells. It has been found that high ROS level corporates in the neurotoxicity of Aβ peptide, which has an essential role in the induction of AD (Sagara et al., 1998; Smith et al., 2000). Main free radicals are produced in the respiration process of mitochondria, as by-products of electron transport and oxidative phosphorylation. Overproduction of free radicals and depletion of antioxidant systems are attributed to the mitochondrial damage and destruction of lipids, proteins and DNA, resulting in cell death (Barnham et al., 2004). Neuropathological factors involved in AD development including senile plaques, synaptic dysfunction and formation of neurofibrillary tangles can also initiate neuronal degeneration (Perl, 2010). The key compartment of senile plaque is Aβ, produced by the proteolytic cleavage of precursor of Aβ. Overexpression and disruption in Aβ clearance, result in Aβ accumulation and may lead to the development of neurotoxicity, mainly through induction of oxidative stress, mitochondrial damage, neurofibrillary tangle formation, apoptosis, disturbance in neural functions, and hyperphosphorylation of tau (Borhani et al., 2017).