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n-3 Fatty Acids: Role in Neurogenesis and Neuroplasticity R. Crupi1, A. Marino2 and S. Cuzzocrea*,1,3 1
Institute of Pharmacology, School of Medicine, University of Messina, Policlinico Universitario, Torre Biologica 98123 Messina Italy; 2Dept of Life Sciences “M. Malpighi”, Section of General Physiology and Pharmacology, University of Messina, Viale F. Stagno D’Alcontres 31, 98166 Messina, Italy; 3University of Manchester, UK Abstract: Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately, mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionally important polyunsaturated n3 fatty acids, -linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti-inflammatory and antiapoptotic effects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurological diseases. aged or damaged neurons and in Alzheimer’s disease. Their effect in cognitive and behavioral functions and in several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus, is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalian brain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood and chronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associated with cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulates synaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review the effect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a new therapeutic approach for neurodegenerative diseases is pointed out.
Keywords: n-3 fatty acids, dentate gyrus, neurogenesis, synaptic plasticity. 1. INTRODUCTION A fatty acid is a carboxylic acid with a long un-branched aliphatic tail chain which can be either saturated, monounsaturated or polyunsaturated. Fatty acids can be subdivided into well-defined families according to their saturation state and structural and functional groups [1]. Saturated fatty acids, such as palmitic acid (16:0) are long-chain carboxylic acids that usually have a number of carbon atoms comprised between 12 and 24, with no double bond. Thus, saturated fatty acids are saturated with hydrogen (since double bonds reduce the number of hydrogens on each carbon). Monounsaturated fatty acids contain only a single double bond. An example of a common monounsaturated fatty acid is oleic acid (18:1). Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. Classes of PUFA Fatty Acids There are three main classes of PUFA, omega-3, omega6 and omega-9 fatty acids, differing in the position of their final carbon bond at the methyl end (e.g. omega-3 PUFA have in common a final carbon-carbon double bond in the omega-3 position; that is, the third bond from the methyl end *Address correspondence to this author at the Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario Via C.Valeria – Gazzi 98100, Messina, Italy; Tel/Fax: ???????????????; E-mail:
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of the fatty acid), and omega-6 PUFAs all have a final carbon-carbon bond in the omega-6 position (Fig. 1). The major omega-3, omega-6 and omega-9 PUFAs are listed in (Fig. 1A), and representations of an omega-3 and an omega-6 PUFA are shown in (Fig. 1B). PUFAs play an important role in maintaining homeostasic conditions and are often referred to as ‘essential fatty acids’. Essentiality implies that the fatty acid not only perform a vital function, but are also required as a dietary nutrient. These molecules must be obtained from dietary since unfortunately the animals are not able to synthesize them de novo. Food Sources of Omega-3 Fish, plant, and nut oils are the primary dietary source of omega-3 fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in cold water fish such as salmon, mackerel, halibut, sardines, tuna, and herring. -linolenic acid (ALA) is found in flaxseeds, flaxseed oil, canola (rapeseed) oil, soybeans, soybean oil, pumpkin seeds, pumpkin seed oil, purslane, perilla seed oil, walnuts, and walnut oil. The health effects of omega-3 fatty acids come mostly from EPA and DHA. ALA from flax and other vegetarian sources needs to be converted in the body to EPA and DHA. Many people do not make these conversions very effectively, however. This remains an ongoing debate in the nutrition community; fish and sea vegetable sources of EPA and DHA versus vegetarian sources of ALA. Other sources of omega-3 fatty acids include sea life such as krill and algae. © 2013 Bentham Science Publishers
2 Current Medicinal Chemistry, 2013, Vol. 20, No. 1
Crupi et al.
A
Fatty Acids
Polyunsaturated Omega-6 linoleic acid LA (18:2mega 6)
Omega-3 -linolenic acid ALA (18:3mega 3) 6 desaturase
octadecatetraenoic acid (18:4omega3)
Saturated
Omega-9 oleic acid OA (18:1mega 9)
Palmitic acid Stearic acid
6 desaturase
octadecadienoic acid (18:2omega9)
linolenic acid GLA (18:3omega6)
elongase
eicosatetraenoic acid (20:4omega3)
Monounsaturated
elongase
dihomo--linolenic acid DGLA (20:3omega6)
5 desaturase
eicosadienoic acid (20:2omega9) 5 desaturase
arachidonic acid AA (20:4omega6)
eicosapentaenoic acid EPA (20:5omega3)
eicosatetrienoic acid MA (20:3omega9)
elongase
docosapentaenoic acid DPA (22:5omega3)
docosatetraenoic acid (22:4omega6)
elongase
(24:5omega3)
(24:4omega6) 6 desaturase
(24:6omega3)
(24:5omega6) - Oxidation
docosahexaenoic acid DHA (22:6omega3)
docosapentaenoic acid (22:5omega6) B
O
3 HO
1 O
4
7
10
13
8
11
16 6
HO
1 Carboxylic acid tail
5
14
1
DHA
19 1
AA
Aliphatic tail
Fig. (1). A) Nomenclature of major omega-3, omega-6 and omega -9 PUFAs. B) Example of an omega-3 PUFA (DHA) and an omega-6 PUFA (AA), showing the position of the final carbon-carbon bond, the carboxylic head and aliphatic tail chain.
Food Sources of Omega-6 For general health, there should be a balance between omega-6 and omega-3 fatty acids. The ratio should be in the range of 2:1 - 4:1, omega-6 to omega-3 - and some health educators advocate even lower ratios. The average diet provides plenty of omega-6 fatty acids, so supplements are usually not necessary. People with specific conditions such as eczema or psoriasis, arthritis, diabetes, or breast tenderness (mastalgia) may want to ask their health care providers about taking omega-6 supplements. Dietary Supplementation and Role of Fatty Acids In the last couple of decades a considerable change in diet and lifestyle has led to a dramatically altered ratio of omega-6/omega-3 fatty acid consumption in many countries around the world [2]. From an evolutionary point of view, humans evolved on a diet with an omega-6/omega-3 ratio of approximately 1-2:1, and this is still the optimum recommended dietary ratio of these fatty acids today [3]. However, the present ratio in Western diets is approximately 15-20:1.
This change is due to an increase in the intake of omega-6 PUFA and a concomitant decrease in the intake of omega-3 PUFA. Dietary fats are digested by lipases (pancreatic enzymes) in the small intestine to form free fatty acids (FFA), monoacylglycerols and glycerol. In a similar manner to other nutrients, short and medium chain fatty acids are absorbed, via capillaries in the intestine, directly into the blood. Longer chain fatty acids in comparison are absorbed into enterocytes (epithelial cells lining the small intestine), which then reesterify the FFAs. The human body cannot synthesize long chain PUFAs de novo. However, longer 20-22 carbon chain PUFAs, like EPA and DHA, can be synthesised from the shorter 18-carbon PUFAs, such as -linolenic acid, through a progressive series of desaturation and elongation steps occurring in the liver [4, 5]. The omega-6 and omega-3 PUFA series share the same biosynthetic enzymes, as summarised in (Fig. 2), and hence these conversions occur competitively between the two series. The short chain omega-3 fatty acids are converted to long chain forms (DHA) with an efficiency of less than 5% in humans, therefore most of these long chain PUFAs must be obtained directly from the diet [6].
n-3 Fatty Acids: Role in Neurogenesis and Neuroplasticity
Current Medicinal Chemistry, 2013, Vol. 20, No. 1
Omega-3 PUFA deficiency has been shown to be a risk factor in many diseases/disorders with high impact, such as cardiovascular disease, cancer, rheumatoid arthritis, asthma, and for cerebral diseases such as stroke [7]. It is unknown whether omega-3 PUFA deficiency (or the concomitant increase in omega-6 PUFA) also limits the body’s own ability to respond to acute neuronal injury, thus leading to a worse outcome. On this basis, the aim of the present review is to focus on the role of n-3 fatty acids on central nervous system, with specific regard to neuropsychiatric disorders and to both neurogenesis and neuroplasticity processes, underlying cognitive functions. O CH3 HO
alpha-Linolenic acid (ALA) 100%
O CH3 HO
Eicosapentaenoic acid (EPA) 20%
O CH3
HO
Docosahexaenoic acid (DHA)
