Nanoparticles As Potential Therapeutic Agents For Alzheimer’S Disease
Globally, and increase in life expectancy has led to a higher number of dementia cases, specially Alzheimer’s Disease (AD), one of the most common forms of neurodegenerative disorders. The progress of AD involves loss of cognition and eventually leads to death. Currently, half a million Canadians suffer from AD, and these numbers are expected to increase sharply in the next 20 years. It is estimated to cost 10 billion dollars annually to care for these AD patients, a significant burden on the Canadian healthcare system and the economy. There is a lack of effective treatment strategies for most of the neurodegenerative diseases, and the increase in their incidence stimulates research investigations in this important field.
Currently, clinical diagnosis of AD is based on progressive loss of memory and impairment in cognition, with final diagnosis of AD requiring post-mortem examination of the brain to determine the severity of the Aβ plaques and neurofibrillary tangles. However, AD treatment strategies that will ultimately be successful will likely need to be introduced in the early stages of the disease. Currently available treatments are not ideal, such as the cholinesterase inhibitors Donepezil and Rivastigmine, considering they only ameliorate the symptoms of the disease.
Two of the neuropathological hallmarks of AD are neurofibrillary tangles of tau protein in neurons, and the formation of Aβ plaques in the extracellular environment of the brain. However, it’s still unclear as to whether Aβ-plaques, neurofibrillary tangles, or both, are a cause or an effect of the neurodegeneration in AD. Neurofibrillary tangles are aggregates of oxidatively - modified and hyperphosphorylated microtubule-associate tau. The Aβ peptide is a product of the amyloid precursor protein (APP), and through a series of cleavage events by α-, γ-, β-secretases, afford the Aβ peptide is predominantly Aβ1-40 or Aβ1-42 (a 40- or 42- residue peptide). Aβ can be found in three general forms in the brain: membrane associated, aggregated, and soluble. Most of Aβ is membrane-associated in healthy individuals, but in individuals with AD the aggregate and soluble forms increase considerably. Soluble Aβ oligomers have been shown to initiate several processes in the brain, such as oxidative stress.
Oxidative stress happens when cellular antioxidant defense mechanisms become overwhelmed by reactive oxygen species (ROS). ROS are generated naturally, and oxidative stress plays a large role in normal aging as well as in neurodegenerative diseases.
Transition metals, such as iron and copper, can facilitate the generation of free radicals, and these metals have been shown to abnormally accumulate in the brain with ADchallenges associated with metal chelation therapy in AD. The Fenton reaction between reduced transition metals and hydrogen peroxide is particularly harmful, as it results in hydroxyl radical, a very reactive species. Copper also interacts with Aβ in an electron transfer reaction that reduces copper (II) to copper (I), enhancing the production of a hydroxyl radical.
Role of metal dyshomeostasis in AD
Recent studies have been focusing in the development of molecule chelating agents that will inhibit metal-promoted damage, promising a strategy for treating diseases associated with localized metal accumulation. minding metals: tailoring multifunctinaol.
Metal ions can attach to ligands to form chelates. When a ligand donates an electron pair to the metal, a bond is formed. Some ligands have just one donor pair of electrons, and attach to the metal ion at one single point (monodentate ligand). Other ligands may donate several pair of electrons and have several points of attachment to the metal ion (polydentate ligand). Chelators in iron and copper toxicity. The idea of using a chelating agent to capture the excess of copper is to prevent the generation of an excessive amount of ROS. If the goal is to use a chelator to treat neurodegenerative disease, a prerequisite is that the chelator must be able to cross the blood-brain barrier (BBB). This barrier is what separates the blood in the brain from the neural tissue. Its function is to restrict neurotoxic material from entering the central nervous system while allowing essential nutrients to pass through it. the blood-brain barrier: bottleneck in brain drug development. In order to croos the BBB, it’s better if the molecule is small, and it must be hydrophobic enough to diffuse through the barrier, yet hydrophilic enough to stay in physiological conditions.
Creating a compound capable of permeating the BBB and binding to a metal ion is not trivial. minding metals: tailoring multifunctinaol. In fact, more than 98% of small molecule drugs cannot cross the BBBthe blodd-brain barrier: bottleneck in brain drug develompemt. The basic 3-hydroxy-4-pyridinone (HL0) framework of deferiprone is a good starting point for drug development due to its high affinity for Cu(II), and low affinity for common biological ions such as sodium, potassium, calcium and magnesium, its antioxidant properties and low toxicity n-aryl-substituted.
Also, the structure is amenable to functionalization by N-substituent variation, which can alter the physical properties of the drug without significant alteration of metal ion binding. The issue of crossing the BBB can be overcome using a glucose molecule that will have a double function. The glucoconjugate has been used by various groups to impart elevated brain uptake n-aryl-substituted. The brain consumes a significant amount of glucose, and needs a mechanism that quickly passes it through the BBB. The BBB has a high concentration of glucose transporters that will recognize the glucose molecules, allowing them to cross the BBB.
The glucose will also act as a protecting group for HL0, masking the metal binding site. Once inside cells, the glucose masking group will be cleaved by β-glucosidase enzymes, releasing the active chelating agent. This approach will prevent systemic metal binding prior to enzymatic cleavage of the sugar. minding metals: tailoring multifunctinaol.
The synthesis and characterization of HL0, as well as the method demonstrating how o add the protecting group are described by Scott L. E. and coworkers. n-aryl-substituted. Perez L. R. and Franz K. showed the conversion of the glucoconjugate prochelator into its metal-binding hydroxypyridinone demonstrating adequate cerebral uptake, proving that this compound is indeed able to cross the BBB. Another interesting fact showed in this study is the ability of this chelator in competing with Aβ for binding copper, and decreasing Aβ aggregation. minding metals: tailoring multifunctinaol. Similar results were also demnosntrated by Scott L. E. and coworkers n-aryl-substituted.
