Kopal Saharia1, Ranjeet Kumar2, Kuldeep Gupta2, Shrilekha Mishra3, Jamuna R Subramaniam4. 1. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India; Department of Bioscience and Biotechnology, Banasthali University, Banasthali Vidyapith, India. 2. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India. 3. Department of Bioscience and Biotechnology, Banasthali University, Banasthali Vidyapith, India. 4. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India; Center for Preclinical and Translational Medicine Research, Central Research Facility, Sri Ramachandra University, Chennai, India.
Abstract
BACKGROUND: With an incidence of 1 in 85 persons above the age of 60 years succumbing to the disease, Alzheimer's disease (AD), has been predicted to create havoc globally. In spite of enormous efforts and exhaustive research, no cure is in sight. Hence, it is critical to unravel the mechanism of AD development/protection and identification of a cure soon. PURPOSE: This study is aimed at investigating the mechanism of reserpine action, which alleviates the toxicity of amyloid beta (Aβ) (AD-causing peptide) in Caenorhabditis elegans [1, 2]. METHODS: Determination of alleviation of Aβ toxicity with reserpine manifested as reduction in progressive paralysis, in the background of GFP reporter driven by the promoter of the FMRFamide neuropeptide, FLP-11 (AD; Pflp-11::GFP) and acetylcholine contribution through aldicarb (which inhibits acetylcholine esterase) treatment. RESULTS: The most significant protection against Aβ toxicity was obtained in the background of Pflp-11::GFP. This protection had 2 components. The promoter of FLP-11 with the reporter GFP, Pflp-11::GFP, per se gave significant protection. Further reserpine treatment provided additional alleviation. Together they could almost eliminate Aβ toxicity. These 2 components of Aβ toxicity alleviation are dependent on acetylcholine levels, as an increase in acetylcholine by aldicarb treatment reduces the protective effect. CONCLUSION: A unique way to alleviate Aβ toxicity is reserpine treatment in combination with Pflp-11::GFP. Reserpine should be evaluated as a potential drug in a pilot study in AD patients. Furthermore, identification of the mechanism of Pflp-11::GFP-mediated reduction in Aβ toxicity is a potential pathway to develop therapeutics for AD.
BACKGROUND: With an incidence of 1 in 85 persons above the age of 60 years succumbing to the disease, Alzheimer's disease (AD), has been predicted to create havoc globally. In spite of enormous efforts and exhaustive research, no cure is in sight. Hence, it is critical to unravel the mechanism of AD development/protection and identification of a cure soon. PURPOSE: This study is aimed at investigating the mechanism of reserpine action, which alleviates the toxicity of amyloid beta (Aβ) (AD-causing peptide) in Caenorhabditis elegans [1, 2]. METHODS: Determination of alleviation of Aβ toxicity with reserpine manifested as reduction in progressive paralysis, in the background of GFP reporter driven by the promoter of the FMRFamide neuropeptide, FLP-11 (AD; Pflp-11::GFP) and acetylcholine contribution through aldicarb (which inhibits acetylcholine esterase) treatment. RESULTS: The most significant protection against Aβ toxicity was obtained in the background of Pflp-11::GFP. This protection had 2 components. The promoter of FLP-11 with the reporter GFP, Pflp-11::GFP, per se gave significant protection. Further reserpine treatment provided additional alleviation. Together they could almost eliminate Aβ toxicity. These 2 components of Aβ toxicity alleviation are dependent on acetylcholine levels, as an increase in acetylcholine by aldicarb treatment reduces the protective effect. CONCLUSION: A unique way to alleviate Aβ toxicity is reserpine treatment in combination with Pflp-11::GFP. Reserpine should be evaluated as a potential drug in a pilot study in ADpatients. Furthermore, identification of the mechanism of Pflp-11::GFP-mediated reduction in Aβ toxicity is a potential pathway to develop therapeutics for AD.
Authors: Alena V Savonenko; Tatiana Melnikova; Andrew Hiatt; Tong Li; Paul F Worley; Juan C Troncoso; Phil C Wong; Don L Price Journal: Neuropsychopharmacology Date: 2011-09-21 Impact factor: 7.853
Authors: Jatinder Singh Sangha; Owen Wally; Arjun H Banskota; Roumiana Stefanova; Jeff T Hafting; Alan T Critchley; Balakrishnan Prithiviraj Journal: Mar Drugs Date: 2015-10-20 Impact factor: 5.118