Current Medicinal Chemistry             1875-533X/16 $58.00+.00 © 2016 Bentham Science Publishers Norma Alva a,* , Ronald Alva b and Teresa Carbonell a a Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain; b Department of Quality Control, Laboratories Hypatia, S.A., Lima, Peru A R T I C L E H I S T O R Y Received: May 20, 2016 Revised: September 09, 2016 Accepted: October 10, 2016 DOI: 10.2174/0929867323666161014 144250 Abstract: In clinical and experimental settings, a great deal of effort is being made to protect cells and tissues against harmful conditions and to facilitate metabolic recovery following these insults. Much of the recent attention has focused on the protective role of a natural form of sugar, fructose 1,6-bisphosphate (F16bP). F16bP is a high-energy glycolytic intermediate that has been shown to exert a protective ac- tion in different cell types and tissues (including the brain, kidney, intestine, liver and heart) against various harmful conditions. For example, there is much evidence that it prevents neu- ronal damage due to hypoxia and ischemia. Furthermore, the cytoprotective effects of F16bP have been documented in lesions caused by chemicals or cold storage, in a decrease in mortal- ity during sepsis shock and even in the prevention of bone loss in experimental osteoporosis. Intriguingly, protection in such a variety of targets and animal models suggests that the mechanisms induced by F16bP are complex and involve different pathways. In this review we will discuss the most recent theories concerning the molecular model of ac- tion of F16bP inside cells. These include its incorporation as an energy substrate, the mecha- nism for the improvement of ATP availability, and for preservation of organelle membrane stability and functionality. In addition we will present new evidences regarding the capacity of F16bP to decrease oxidative stress by limiting free radical production and improving anti- oxidant systems, including the role of nitric oxide in the protective mechanism induced by F16bP. Finally we will review the proposed mechanisms for explaining its anti-inflammatory, immunomodulatory and neuroprotective properties. Keywords: Fructose 1,6-bisphosphate, calcium chelator, neuroprotection, anticonvulsant, immunoprotection, oxi- dative stress, antioxidant, osteoporosis. 1. INTRODUCTION Fructose 1,6-bisphosphate (F16bP) is a naturally occurring sugar and the first chemical intermediate dis- covered in fermentation. It was originally named Harden-Young ester by the biochemistry scientists who discovered it accidentally while performing cell-free fermentation experiments at the beginning of the 20th century [1]. F16bP is a high-energy endogenous inter- mediate of the glycolytic pathway and is produced by *Address correspondence to this author at the Department of Cellu- lar Biology, Physiology and Immunology, Faculty of Biology, Uni- versity of Barcelona, P.O. Box: 08028, Barcelona, Spain; Tel+34-934-039-635; Fax: +34-934-110-358; E-mail: nvalva@ub.edu. the phosphofructokinase-1 activity through phosphory- lation of fructose 6-phosphate. The β -D-form of this molecule is very common in cells. In fact, most glucose and fructose will be converted to fructose 1,6- bisphosphate just after entering a cell. Interest in studying F16bP has recently increased due to mounting evidence of its beneficial effects. Di- verse in vitro and in vivo studies suggest that F16bP induces protection of cells and tissues against a wide variety of harmful conditions, and it may play a direct role in the regulation of many metabolic pathways. Currently, the MeSH Pharmacological Classification includes F16bP as a protective compound in the fol- lowing categories: neuroprotective agents, immu- Send Orders for Reprints to reprints@benthamscience.ae 4396 Current Medicinal Chemistry, 2016, 23, 4396-4417 REVIEW ARTICLE Fructose 1,6-Bisphosphate: A Summary of Its Cytoprotective Mecha- nism