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Curcumin Effects On Astrocytes in common Neurodegenerative Disease

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ALS is the most prominent adult motor neuron disease (11) and almost completely fatal neurodegenerative disease. It is also classified as a motor neuron disease described by both upper and lower motor neurons involvement (162). Approximately a quarter of the inherited patients are as a result of missense mutations in the ubiquitously expressed enzyme superoxide dismutase 1 (SOD1), that its enzymatic activity leads to destroy the superoxide, a highly reactive oxygen (11).

Additionally, mutation in other genes such as dynactin, alsin and senataxin are involved in familial ALS (34). ALS patients can categorize in to two groups associated with the spinal onset or bulbar onset. Bulbar symptoms, is the initial exhibition of disease in about 30% of patients including dysarthria and dysphagia[3] and the onset site is a key disease prognostic factor, for example patients with bulbar-onset ALS have been shown a worse prognosis than the others (162, 163). Moreover, oxidative stress, mitochondrial dysfunction, and neuroinflammation are pathologically involved in ALS (162).

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Neuroinflammation via activation of the nuclear factor ĸβ (NF- ĸβ) pro-inflammatory cellular pathway has an important role in ALS pathogenesis (27) . Some case of ALS increases NF-ĸβ signaling expression in microglia (13). Thus Decreased expression of NF-ĸβ in microglia can slow progression and lengthen survival in several ALS mouse models (14–16). Astrocytic glutamate transporters have an essential importance in the motor neurons protection against glutamate excitotoxicity.

Astrocytic GLT-1/EAAT2 glutamate transporters and activity are lost in SOD1 mutant animals and human patients and it is possible consequence of ALS (164, 165). Fortunately, β-lactam antibiotics such as ceftriaxone through transcriptional stimulation upregulate the GLT-1/EAAT2 transporter finally lead to prolonged survival in ALS mice (166). Curcumin has key role in decreasing the activation of NF-ĸβ pathway activation in rat and mouse microglial cell cultures (17–19) and in rat brain when delivered to the animals via intraperitoneal injection (20) or orally (21). Furthermore, curcumin can decrease NF-kB activation in human cell lines (22–25).

Despite the promising preclinical data, a clinical trial, with cancer patients, utilizing a high bioavailability oral form of curcumin (Theracurmin) could not find a change in NF-kB levels in peripheral blood monocytes (26). Reduce expression of NF-ĸβ in microglia slows progression and extends survival in multiple mouse models of ALS (14–16). Curcumin can decrease NF-ĸβ pathway in rat and mouse microglial cell cultures (167) and also apparently declines NF-kB activation in human cell lines (167). Oxidative stress has critical roles in ALS pathology (168) and patient revealed an increased oxidative species that is correlated with disease severity, and reduced antioxidants in their blood (35). Compound that induce an antioxidant pathway named Nrf2-ARE, can postpone disease progression some mouse model of ALS (169).

Furthermore, Curcumin has key function in free radicals (ROS) neutralization in vitro (170) and also can stimulate the Nrf2-ARE pathway in the rat’s brain (171), skeletal muscle of mice (172) and rats and isolated rat astrocytes (173). SOD1 Misfolded proteins (‘‘aggregates’’), are present in the motor neurons of PALS plays several important pathogenic roles (174). misfolded protein targeting as Treatments can postpone ALS progression of animal models (175). As already an earlier, curcumin can inhibit SOD1 aggregation in vitro (176), but, the curcumin concentrations that were used in this research was so high and these concentrations wouldn’t be possible to obtain in humans. Curcumin can also stimulate protein aggregates clearance related gene expression in PALS and Alzheimer’s disease blood cells (177).

Fortunately, three PALS examination confirms the motor enhancement because regimens including curcumin (although there are several alternative explanations for these improvements) and there is one small pilot trial showing some benefit of curcumin in PALS (27, 35, 168, 178).

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