Natural Products and Their Active Principles Used in the Treatment of Neurodegenerative Diseases: a Review

Oriental Pharmacy and Experimental Medicine (2019) 19:343–365 https://doi.org/10.1007/s13596-019-00396-8 REVIEW Natural products and their active principles used in the treatment of neurodegenerative diseases: a review Mehnaz Kamal1 · Mamuna Naz2 · Talha Jawaid3 · Muhammad Arif4 Received: 11 April 2017 / Accepted: 28 August 2019 / Published online: 18 September 2019 © Institute of Korean Medicine, Kyung Hee University 2019 Abstract Free radicals are the byproducts of physiological aerobic cellular metabolism. Intrinsic antioxidant system plays its pivotal function in prevention of any loss due to free radicals. Though, incorporation or excess production of free radicals from environment to living system or imbalanced defense mechanism of antioxidant system leads to severe consequences like neuro-degeneration. Sensory or functional loss occurs in neural cells in neurodegenerative diseases. Besides numerous other genetic or environmental factors, oxidative stress is the major cause which leads to damage of neurons and production of neurodegenative diseases. However, oxygen is vital for existence, excessive reactive oxygen species production and imbalanced metabolism leads to a variety of diseases such as aging, Parkinson’s disease, Alzheimer’s disease, and many other neurodegenative diseases. Free radicals toxicity contributes to DNA and proteins damage, tissue damage, infamma- tion and consequent cellular apoptosis. Neuroprotection is a broad term commonly used to refer therapeutic strategies that can prevent, delay or even reverse neuronal damage. Since thousands of years, lots of medicinal plants have been used in a group of herbal preparations of Ayurveda (Indian traditional health care system) named Rasayana because of the antioxidant principles present in it, responsible for their medicinal use in neurodegenerative diseases. This work constitutes a literature review on natural products contain antioxidant principles used in the treatment of neurodegenerative disease. Keywords Oxidative stress · Neurodegenerative diseases · Natural products · Antioxidant principles Introduction their outer most shell. These species are very reactive and unstable (Gilbert et al. 2000). They are produced in nor- Oxidative stress is a state in the body in which the oxidation mal cellular procedures like arachidonic acid metabolism, exceeds the antioxidant system due to the loss of balance phagocytosis, mitochondrial respiratory chain, fertilization between them (Yoshikawa and Naito 2000). Free radicals and ovulation. In pathological conditions, their production are those chemical species which have unpaired electron in multiplies several times. Oxygen free radicals involve superoxide, alkoxyl, hydroxyl, peroxyl, hydroperoxyl, nitric oxide, * Mehnaz Kamal hypochlorous acid, hydrogen peroxide, hyypobromous acid, [email protected] and peroxynitrite (Evans and Halliwll 2001). Species pos- sessing oxygen are called reactive oxgen species (ROS) and 1 Department of Pharmaceutical Chemistry, College those containing nitrogen are termed as reactive nitrogen of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box No. 173, Al-Kharj 11942, Kingdom of Saudi Arabia species (RNS) (Table 1). Alkoxy and hydroxyl free radicals are highly reactive and they rapidly attack cellular mac- 2 Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box No. 173, romolecules (Boveris et al. 1972). Nitric oxide, superox- Al-Kharj 11942, Kingdom of Saudi Arabia ide anion and lipid hydroperoxides are comparatively less 3 Department of Pharmacology, College of Medicine, reactive. Al Imam Mohammad Ibn Saud Islamic University, If there is excessive production of free radicals or P.O. Box 5701, Othman Ibn Afan Street, Riyadh 11432, decreased production of anti-oxidants in the body this can Kingdom of Saudi Arabia lead to a state in the body called oxidative stress. Oxida- 4 Department of Pharmacognosy, Faculty of Pharmacy, tive stress can be useful or harmful in the body depend- Integral University, Dasauli, Kursi Road, Lucknow, ing upon the condition. For example sometime oxidative Uttar Pradesh 226 026, India Vol.:(0123456789)1 3 344 M. Kamal et al. Table 1 ROS and RNS Cellular targets of ROS in the body Reactive oxygen species Reactive nitrogen species Following three are the main targets of oxidative damage 2.− − O Superoxide radical ONOO Peroxynitrite through free radicals (Valko et al. 2006; Halliwell and Gut- H2O2 Hydrogen peroxide ROONO Alkyl peroxynitrites teridge, 1999; Marnett 1999; Siems et al. 1995; Stadtman OH· Hydroxyl radical N2O3 Dinitrogen trioxide 2004; Wang et al. 1996). HOO· Hydroperoxyl radical HNO2 Nitrous acid − LOOH Alkylhydroperoxide NO Nitroxyl anion (a) Lipids (lipid peroxidation) LOO· Alkylperoxyl radical NO· Nitric oxide (b) DNA (DNA damage) − HOCl Hypochlorous acid NO2Cl Nitryl chloride (c) Proteins (protein damage) Lipid peroxidation stress is induced in the body for the sake of preparing birth canal for delivery. In normal physiological function ROS can induce lipid peroxidation and can alter the arrange- oxidative stress can lead to various pathophysiological ment of lipid bilayer membrane by increasing membrane abnormalities including cardiovascular disease, neuro- permeability, promoting the efux of solutes in the cytosol toxicity, hepatotoxicity, nephrotoxicity, diabetes mellitus, and inactivating membrane bound enzymes and receptors atherosclerosis, hypertension, malignancies and autoim- (Girotti 1985). In lipid peroxidation process polyunsaturated mune diseases (Yoshikawa and Naito 2000). fatty acids (PUFAs) present in the phospholipid layer of cell membrane react with the oxygen yielding hydroperoxides (LOOH). As a result of lipid peroxidation various products Sources of ROS and RNS are generated including aldehydes and epoxides. Malondi- aldehyde (MDA), which is a product of lipid peroxidation Endogenous (Cellular location) Lysosomes, membrane form protein cross-linkages and inactivates cellular proteins lipid bilayers, mitochondria, endoplasmic reticulum, per- (Siu and Draper 1982; Esterbauer et al. 1984; Hagihara et al. oxisomes etc. (Fig. 1). 1984). Exogenous Drugs, pesticides, tobacco smoke, anesthet- ics, radiation, industrial pollutants, organic solvents, high DNA damage oxygen in surrounding etc. ROS can damage the DNA by several mechanisms involv- ing degradation of DNA bases, mutation, cross linking with Fig. 1 Endogenous sources of ROS and RNS in the cell 1 3 Natural products and their active principles used in the treatment of neurodegenerative… 345 proteins, deletion or mutation, sugar bound modifcations Oxidative stress in Neurodegenerative disorders etc. Oxidation of DNA also oxidizes the DNA bases. Exces- sive damage to DNA due to oxidation can cause the cancer. Neurodegeneration is the progressive loss of neuronal struc- DNA damage can also occur due to RNS. Changes in DNA ture and function. Human nervous system is the most meta- due to oxidative stress can produce the mutation in DNA. bolically active organ; it consists of brain, spinal cord and Among DNA bases guanine is more susceptible to oxidation peripheral nerves which contain rich amount of iron and and can form multiple oxidized products. The most impor- unsaturated fatty acids. In order to perform normal body tant modifcations of DNA are 8-oxo-7,8-dihydroguanine functions it needs continuous oxygen rich blood supply. and 2,6-diamino-4-hydroxy-5-formamidopyrimidine. Due to Consumption of higher quantity of oxygen leads to the pro- addition of hydroxyl radical to carbon 8 position of guanine duction of higher number of ROS or RNS. Central nerv- ring this occurs. 8-oxoGua is the most abundant oxidative ous system consumes high amount of oxygen but is lacking product found in the DNA oxidation products and is also in enzymes which metabolize oxygen based reactants into considered as the biomarker of oxidative stress. Some modi- harmless species (Halliwell 2001). Central nervous system fcations in DNA can lead to aging, cardiovascular diseases, also consists of excessive amount of polyunsaturated fatty carcinogenesis, neurodegenerative diseases and autoimmune acids (PUFA’s) which can be oxidized by harmful ROS diseases (Birben et al. 2012). (Nunomura et al. 2006). Another drawback is the presence of blood brain barrier (BBB), which protects the brain by limiting the difusion of some toxins into glia and neurons Protein damage but they also reduce the uptake of some antioxidants into the brain, hence making the brain more prone to destruction Various cellular proteins are afected by oxidative stress, by free radicals or reactive oxygen species. Oxidative stress these proteins include: kinases, phosphatases, metabolic is a major factor involved in neurogeneration (Fig. 3). The enzymes and transcription factor. Oxidation of cellular pro- loss of neurons can be result of either decreased antioxidant teins can alter the homeostasis of the cell as it can afect the supply or increased free radical production or both. Some cell structure, cell signaling, and enzymatic processes of the recent studies have suggested the oxidative stress to be the cell. Some proteins have more susceptibility to oxidative primary cause of neurodegenerative diseases. stress than others, for example mitogen activated protein Neurodegenerative diseases (NDDs) are the CNS disor- kinase 6, protein tyrosine phosphatase and nuclear factor-1 ders characterized by the damage of neurons and sometime transcription factor, all these have cysteines

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