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  • Granzyme B Inhibitor Z-AAD-CH2Cl receptor br Transparency do


    Transparency document
    Introduction Cigarette smoke is modifiable factors to alter the neurovascular functions. Now a day, cigarette smoking in public place is offense due to toxic exposure cause the neurological and respiratory system damage to non-smoker population [1]. A literature survey expressed that worldwide six millions of peoples are dying every day by cigarette smoke exposure. The chronic cigarette smokers are shown lung cancer, ischemic heart disease, atherosclerotic diseases leads to produce the fatal morbidities [2]. And, it also causes the neurocognitive function leads to decreased quality of life. Thus, the strong interconnection between smoking and neurovascular complications like vascular dementia, multiple sclerosis, Alzheimer\'s disease, and neurodevelopmental damage are observed. Moreover, cigarette smoke triggers the blood-brain barrier and neuroimmune functions [3]. The cigarette smoke has numerous cytotoxic chemicals like carbon monoxide, nitrosamines, aryl hydrocarbon, phenolic and polynuclear aromatic compounds [4]. It is known to cause the neuroendocrine alteration and initiation of the neurodegenerative process [5]. Furthermore, cigarette smoke causes the neuronal death by the accumulation of free radicals, activation of neuroglial cells, sustained ion channels opening and enhancement of neuronal plasticity [6]. Hence, it causes critical complications to neurovascular systems. Neurovascular systems are controlled by various peptides. Endothelin peptide is major peptides for the neurovascular function and it is generated by activation of endothelin converting enzymes. Endothelin peptide has a diversifiable function in the neurovascular system via regulation of endothelin-A and endothelin-B receptors [7]. There are numerous reports are documented that, the administration of endothelin-A receptor antagonist possess the neurovascular protective actions and enhancement of memory functions [8]. The exposure of cigarette smoke also accelerates the neurovascular complication via activation of endothelin receptors. However, the role of selective endothelin-A receptor antagonist in cigarette smoke-induced neurovascular complications and memory dysfunction is not explored yet. Donepezil is an Granzyme B Inhibitor Z-AAD-CH2Cl receptor esterase (AChE) inhibitors and it regulates the cholinergic neurotransmitters functions. It is widely used medicine for cognitive disorders. And, it has free radical scavenging, reduction of peroxidation of membrane lipids, anti-inflammation and neurovascular protective actions [9]. Therefore, the present research work designed to explore the role of ambrisentan (selective endothelin-A receptor antagonist) in CSE-induced memory impairment in Danio rerio.
    Materials and methods
    Discussion The data of the present study showed that, treatment of ambrisentan (2.5 and 5 mg/kg; i.p.) ameliorates the CSE exposure induced cognitive impairment. The ambrisentan shown cognitive improvement against CSE exposure induced decrease TSLC and increase NEDC values in light and dark chamber (Fig. 1A and B); decreased TSGC values and increased NERC values in color recognition test (Fig. 2A and B) (ii) decreased percentage of ETC and TSTC values in partition preference test (Fig. 3A and B) (iii) decreased TSUS values and increased TSLS values in horizontal compartment test (Fig. 4A and B) (v) increased TL and decreased percentage of TCP values in T-maze tests (Fig. 5A and B). In addition, ambrisentan also produces attenuation of CSE induced biomarkers changes. These results were similar to that of donepezil treatment. Cigarette smoking plays a chief risk factor in various neurovascular complications [21]. The mechanism of CSE induced neurovascular complications are activates the immune cells like glial cells, dendritic cells, mast cells and so on [22]. In addition, it also alters the cellular metabolic pathways lead to generate abundant free radicals via mitochondrial dysfunction. Further, it alters the cytosolic ion concentration via open the ion channels and enhances the excitatory amino acid receptors functions [23]. These actions intensified the long-term-potentiation via neuronal firings [24]. Subsequently, it alters the nuclear, mitochondria, endoplasmic reticulum and cellular membrane proteins (lipid peroxidation) and minimizes the reduced glutathione level [25]. The exposure of cigarette smoke and their condensate has additional effect i.e., alteration of neurotransmitters including acetylcholine levels via modulation of acetylcholinesterase (AChE) activity [[26], [27]]. The raising AChE activity level by CSE induces memory dysfunction [26]. The exact molecular mechanism of CSE in AChE activity is not clear yet. However, CSE alters the amyloid peptide pathway with the interference of AChE activity leads to alleviating the Alzheimer\'s disease [[28], [29]].