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  • AD is a major neurological disorder

    2021-10-13

    AD is a major neurological disorder, usually effecting the elderly population, which is difficult to diagnose until symptoms begin to accumulate. As of 2013, approximately five million Americans were living with AD. The number with this disease is projected to be 16 million by 2050 (Hebert et al., 2013). The progression of AD is divided clinically into asymptomatic, to a gradual decline of memory and cognitive ability, eventually leading to dementia. The disease can be difficult to diagnose but the increase in the levels of biomarkers (abnormal levels of amyloid-β and total and phosphorylated tau proteins) can confirm the diagnosis of AD. Progression of AD can take several years and current treatments focus on maintaining function or improving quality of life since there is no cure (Rao et al., 2013). One common feature of both of these diseases is the death of cells, particularly neurons (Dineley and Denner, 1999). Both of them are associated with apoptosis, generation of reactive oxygen species and oxidative stress (Behl and Moosmann, 2002). The peptide under investigation here is IRL-1620 is an endothelin B (ETB) receptor agonist. Endothelin (ET) is an endogenous vasoregulatory peptide which acts at two receptors: ETA and ETB. ETA receptors are mainly located on vascular smooth muscle cells and mediate vasoconstriction, whereas ETB receptors are mainly located on vascular endothelial cells and mediate vasodilatation. It has been demonstrated previously by our research group that the activation of ETB receptors with intravenously administered IRL-1620 results in a significant elevation in cerebral blood flow in healthy rats (Leonard and Gulati, 2009). IRL-1620 [Suc [glu9, Ala11, 15]-endothelin-1(8–21)] (molecular weight 1820) (Fig. 1), is a peptide with 15 long way and is a linear analog of ET-1 (8–21). IRL-1620 is also under clinical development (Phase I: NCT00613691; Phase II: NCT01741155) as an adjuvant for the treatment of solid tumors. IRL-1620 acts by agonizing the ETB receptor and hence controlling the local blood flow in the brain. By decreasing oxidative damage during apoptosis; it has been shown to be neuroprotective to cells. IRL-1620 has been previously studied as an effective treatment for cerebral ischemia by increasing the blood flow to the damaged areas of the brain (Leonard et al., 2012). Rats with stroke induced by occlusion of the middle cerebral artery which were treated with IRL-1620 showed improved neurological and motor function compared to vehicle-treated rats (Leonard et al., 2012). Another mechanism by which IRL-1620 was found to be neuroprotective is by stimulation of an increased proliferation of neuronal cells and vascular growth. Stimulation of the ETB receptor increases the expression of vascular endothelial growth factor (VEGF), which promotes angiogenesis, and also stimulates release of NGF, which promotes nerve growth (Leonard and Gulati, 2013). The protective effects of IRL-1620 were found to be beneficial as a treatment for AD by preventing apoptosis of neuron cells from oxidative damage (Briyal et al., 2014). IRL-1620 was found to reduce infarct volume, edema, neurological and motor deficits, oxidative stress for up to 1week following stroke. It was found to increase cerebral blood flow (Leonard et al., 2011, Leonard et al., 2012) and increase angiogenesis and neurogenesis (Leonard and Gulati, 2013). The effect of IRL-1620 in Aβ (1–40)-induced impairment of learning and memory process using Morris Water Maze tests and oxidative stress parameters was studied (Briyal et al., 2014). Aβ-induced impairment of learning and memory was evidenced by significantly longer escape latencies and no preference for the quadrant which previously contained the platform in the probe trial, however treatment with IRL-1620 significantly reversed these effects. In recent studies by our group administration of IRL-1620 to rodent AD model was found to enhance number of blood vessels labeled with VEGF and enhanced ETB, VGEF and NGF expression (Briyal et al., 2015). The study confirmed IRL-1620 improved both acquisition (learning) and retention (memory) in water maze task and its angiogenic and neurogenic potential and suggested its application in neurovascular degenerative disorders such as AD.