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Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems ELENI BAGLI 1,2 , ANNA GOUSSIA 3, MARILITA M

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Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems ELENI BAGLI 1,2 , ANNA GOUSSIA 3, MARILITA M in vivo 30 : 535-548 (2016) Review Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems ELENI BAGLI 1,2 , ANNA GOUSSIA 3, MARILITA M. MOSCHOS 4, NIKI AGNANTIS 3 and GEORGIOS KITSOS 2 1Institute of Molecular Biology and Biotechnology - FORTH, Division of Biomedical Research, Ioannina, Greece; 2Department of Ophthalmology, University of Ioannina, Ioannina, Greece; 3Department of Pathology, University of Ioannina, Ioannina, Greece; 4Department of Ophthalmology, University of Athens, Athens, Greece Abstract. Neurodegeneration characterizes pathologic pathological events, including oxidative stress, mitochondrial conditions, ranging from Alzheimer’s disease to glaucoma, dysfunction, inflammation and protein aggregation (2, 3). with devastating social and economic effects. It is a The increasing knowledge of the cellular and molecular complex process implicating a series of molecular and events underlying the degenerative process has greatly cellular events, such as oxidative stress, mitochondrial stimulated research for identifying compounds capable of dysfunction, protein misfolding, excitotoxicity and stopping or, at least, slowing the progress of neural inflammation. Natural compounds, because of their broad deterioration. spectrum of pharmacological and biological activities, Natural compounds are complex chemical multiple-target could be possible candidates for the management of such molecules found mainly in plants and microorganisms (4). multifactorial morbidities. However, their therapeutic These agents have been extensively studied regarding their potential against neurodegenerative diseases has been antioxidant activities. However, in addition to their ability hampered by their poor bioavailability and subsequent to prevent damage caused by oxidative stress, they have insufficient delivery to the brain. This article provides an been shown to modulate multiple signal transduction overview of the molecular mechanisms through which pathways through direct effects on enzymes, such as natural compounds exert their neuroprotective effects, as kinases, regulatory proteins and receptors (4, 5). well as the development of novel natural compound- Furthermore, it has been suggested that many polyphenols loaded delivery systems that could improve their exert some of their beneficial biological effects via neuroavailability. chromatin remodeling and epigenetic modifications (6). This broad spectrum of pharmacological or biological Neurodegenerative diseases are characterized by progressive activities has made them suitable candidates for the loss of structure or function of neurons and include a broad treatment of multifactorial diseases, such as cancer and range of conditions, from Parkinson ’s (PD), Alzheimer ’s neurodegenerative diseases (7-9). Indeed, there are studies (AD), Huntington ’s disease (HD) to glaucoma (1). They suggesting a correlation between consumption of represent rapidly growing causes of disability and even flavonoids and low population rates of dementia (10). death, having profound social and economic implications. However, their physicochemical properties are not drug- Neurodegeneration is the result of a complex cascade of like and a number of challenges, concerning their stability and neuroavailability, need to be overcome in order to be established as effective therapeutics. This review focuses on the neuroprotective role that Correspondence to: Georgios Kitsos, Department of natural compounds have through different molecular Ophthalmology, University of Ioannina, Stavros Niarchos Avenue, mechanisms on the biological processes involved in 45500 Ioannina, Greece. Tel: +302651099657, Fax: +30 26510 07077, e-mail: [email protected] neurodegenerative diseases. Furthermore, the development of novel delivery systems, that could improve the Key Words: Neuroprotection, neurodegeneration, natural compounds, neuroavailability and subsequently the neuroprotective flavonoids, drug delivery systems, degenerative diseases, review. activity of the natural compounds, is discussed. 0258-851X/2016 $2.00+.40 535 in vivo 30 : 535-548 (2016) Neuroprotective Targets of Natural Compounds dependent superoxide dismutase ( Mn-SOD ) and modulates uncoupling protein 2 (UCP2) protein levels in mitochondrial Mitochondrial Dysfunction membranes, both important in the redox maintenance of the organelle, possibly through SIRT1 activation (24, 27). It has Neurons are heavily dependent on mitochondria for survival also been shown in different in vivo and in vitro experimental because of their high energy requirement. Mitochondria are models that the AMPK–SIRT1 pathway plays a pivot role in important in various essential cellular functions, including RSV-induced neuroprotection (28-30). Furthermore, co- apoptosis, metabolism and calcium homeostasis. Regarding administration of EGCG and RSV reversed the severe oxidative stress, they are both an important source of impairment of mitochondrial bioenergetics and biogenesis in reactive oxygen species (ROS) production and a major target hippocampal progenitor cells from a Down syndrome mouse for ROS-induced cellular injury. Given the role of model via activation of the AMPK/Sirt1/PGC-1 α axis as well mitochondria as key regulators of cellular death and life, it (31). Finally, the neuroprotective role of viniferin, a stilbene is expected that alterations in their biology have implications RSV dimer, in an HD model was shown to be mediated in a wide array of diseases, such as neurodegenerative ones through the AMPK/SIRT3 pathway (32). (11-13). A direct link between mitochondrial dysfunction and Concerning anti-neoplastic agent-induced neurotoxicity, neurotoxic manifestations of anticancer drugs has also been natural compounds have also been studied. Co- established (14). administration of curcumin (CUR) and QCT mitigated SIRT1, a sirtuin protein family member, is a nicotinamide peripheral neurotoxicity induced by oxaliplatin through the adenine dinucleotide (NAD)(+)-dependent histone and protein restoration of glutathione S-transferase (GST), glutathione deacetylase. A large number of studies have reported that peroxidase (GPx) and MnSOD activity (11, 14, 33). activation and overexpression of SIRT1 are neuroprotective Neurodegeneration, as a complication of diabetes, it is in both acute central nervous system (CNS) injuries and known to be associated with dicarbonyl glycation and chronic neurodegenerative diseases (15). AMP-activated methylglyoxal (MGO), a major precursor of advanced protein kinase (AMPK) enhances SIRT activity by increasing glycation end products (AGEs), which target mainly cellular NAD+ levels leading to the deacetylation and mitochondrial proteins. Several in vivo and in vitro studies modulation of the activity of downstream SIRT1 targets like have pointed out that flavonoids could inhibit the formation peroxisome proliferator-activated receptor-gamma coactivator of AGEs and prevent diabetic neurodegeneration (34, 35). 1 alpha (PGC-1 α) (16), a master regulator of mitochondrial Moreover, myricitrin was shown to alleviate MGO-induced biogenesis (17). Therefore, the AMPK/SIRT1/ PGC-1 α axis mitochondrial dysfunction, possibly through modulation of is strongly related to the orchestration of mitochondrial the AGEs/Receptor for AGEs (RAGE)/Nuclear factor kappa function and energy/redox status in mammalian cells. B (NF-kappaB) pathway (36). Nature has been a major source of substances that can improve mitochondrial function (18). Among them Apoptosis polyphenols, such as luteolin, myricitrin, quercetin (QCT) and epigallocatechin gallate (EGCG) have been extensively Apoptotic neuronal death is a common feature in the brain studied regarding their beneficial effects on mitochondrial of patients suffering from many neurodegenerative diseases function both in vitro and in vivo (19-22). In addition to and either intrinsic (mitochondrial-mediated) or extrinsic these, proanthocyanidins, a group of polyphenolic (death receptor-mediated) (37) is controlled by several bioflavonoids, ameliorate the hydrogen peroxide-induced proteins (38). The Bcl-2 protein family plays an essential mitochondrial dysfunction via stimulating the mitochondrial role in the regulation of the intrinsic pathway via monitoring membrane potential (MMP) and respiratory chain complex mitochondrial membrane permeability and the release of the IV, while moderating the mitochondrial free radical pro-apoptotic factor, cytochrome c, which promotes the production, ROS and mitochondrial superoxide (23). Also, caspase-9 activation (39, 40). Bcl-2 proteins include hesperidin has been reported to enhance the mitochondrial members that inhibit apoptosis (such as Bcl-2, Bcl-w, Bcl- complex I-IV enzymatic potential (22). On the other hand, xL, Mcl-1) or promote apoptosis (such as Bak, Bad, Bax, resveratrol (RSV) may act directly or indirectly on the Bcl-rambo). It is the balance between these members that mitochondria with subsequent beneficial effects (reviewed determines whether or not a cell will undergo apoptosis. On by de Oliveira et al. (24)). The mechanism by which RSV the other hand, the caspase cascade may be initiated at the modulates mitochondrial function is through regulation of endoplasmic reticulum (ER) as well (40) by stress cell signaling pathways and genes involved in mitochondrial conditions, which affect the folding of proteins in ER lumen biogenesis, endogenous antioxidant defense and oxidative (41, 42). Finally, in addition to ER-resident proteins and phosphorylation (25, 26).
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