Maternal omega-3 fatty acid supplementation on vitamin B12 rich diet improves brain omega-3 fatty acids, neurotrophins and cognition in the Wistar rat offspring


      Introduction: The consequences of wide spread vegetarianism due to low vitamin B12 on brain development and functioning is gaining importance. However, there are no studies which have evaluated exclusively vitamin B12 supplementation during pregnancy on brain growth. A series of our animal studies have documented adverse effects of maternal micronutrient imbalance on brain neurotrophins and its amelioration by omega-3 fatty acids. Therefore, the present study investigated the effect of maternal supplementation with vitamin B12 alone and B12 plus omega-3 fatty acid on pup brain fatty acids and neurotrophins at birth and 3 mo of age. Methods and results: Pregnant Wistar rats and their male offspring were assigned to 3 dietary groups: Control (normal vitamin B12 (25 μg/kg), vitamin B12 supplemented (BS) (50 μg/kg), vitamin B12 supplemented with omega-3 fatty acid (BSO) till 3 month of age. Maternal vitamin B12 supplementation (BS) increased brain BDNF (protein and mRNA) and DHA levels in pups at birth and in the hippocampus at 3 month of age (BDNF only). These effects were further enhanced by omega-3 fatty acid supplementation to vitamin B12 supplemented group. The spatial memory performance was found to be enhanced in BSO group which was characterised by less number of errors in radial eight arm maze. Conclusion: Our results indicate that a combination of omega-3 fatty acid and vitamin B12 enriched diet may exert beneficial effects on synaptic plasticity and cognition, which may prove beneficial for mental health, particularly in preventing neurocognitive disorders.



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        • Dror D.K.
        • Allen L.H.
        Interventions with vitamins B6, B12 and C in pregnancy.
        Paediatr Perinat Epidemiol. 2012; 26: 55-74
        • Benton D.
        • ILSI Europe a.i.s.b.l
        Micronutrient status, cognition and behavioral problems in childhood.
        Eur J Nutr. 2008; 3: 38-50
        • Pawlak R.
        • Parrott S.J.
        • Raj S.
        • Cullum-Dugan D.
        • Lucus D.
        How prevalent is vitamin B (12) deficiency among vegetarians?.
        Nutr Rev. 2013; 71: 110-117
        • Yajnik C.S.
        • Lubree H.G.
        • Thuse N.V.
        • Ramdas L.V.
        • Deshpande S.S.
        • Deshpande V.U.
        • et al.
        Oral vitamin B12 supplementation reduces plasma total homocysteine concentration in women in India.
        Asia Pac J Clin Nutr. 2007; 16: 103-109
        • Gammon C.S.
        • von Hurst P.R.
        • Coad J.
        • Kruger R.
        • Stonehouse W.
        Vegetarianism, vitamin B12 status, and insulin resistance in a group of predominantly overweight/obese South Asian women.
        Nutrition. 2012; 28: 20-24
        • Bhate V.
        • Deshpande S.
        • Bhat D.
        • Niranjan J.
        • Ladkat R.
        • Watve S.
        • et al.
        Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children.
        Food Nutr Bull. 2008; 29: 249-254
        • Roy S.
        • Kale A.
        • Dangat K.
        • Sable P.
        • Kulkarni A.
        • Joshi S.
        Maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids: implications for neurodevelopmental risk in the rat offspring.
        Brain Dev. 2012; 34: 64-71
        • Sable P.
        • Dangat K.
        • Kale A.
        • Joshi S.
        Altered brain neurotrophins at birth: consequence of imbalance in maternal folic acid and vitamin B12 metabolism.
        Neuroscience. 2011; 190: 127-134
        • Sable P.S.
        • Dangat K.D.
        • Joshi A.A.
        • Joshi S.R.
        Maternal omega 3 fatty acid supplementation during pregnancy to a micronutrient-imbalanced diet protects postnatal reduction of brain neurotrophins in the rat offspring.
        Neuroscience. 2012; 217: 46-55
        • Wu A.
        • Ying Z.
        • Gomez-Pinilla F.
        Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition.
        Neuroscience. 2008; 155: 751-759
        • Makrides M.
        DHA supplementation during the perinatal period and neurodevelopment: do some babies benefit more than others?.
        Prostaglandins Leukot Essent Fatty Acids. 2013; 88: 87-90
        • Carlson S.J.
        • Fallon E.M.
        • Kalish B.T.
        • Gura K.M.
        • Puder M.
        The role of the ω-3 fatty acid DHA in the human life cycle.
        JPEN J Parenter Enteral Nutr. 2013; 37: 15-22
        • Kanoski S.E.
        • Davidson T.L.
        Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity.
        Physiol Behav. 2011; 103: 59-68
        • Dauncey M.J.
        Genomic and epigenomic insights into nutrition and brain disorders.
        Nutrients. 2013; 5: 887-914
        • Kulkarni A.
        • Dangat K.
        • Kale A.
        • Sable P.
        • Chavan-Gautam P.
        • Joshi S.
        Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats.
        PLoS One. 2011; 106: e17706
        • Dhobale M.
        • Chavan P.
        • Kulkarni A.
        • Mehendale S.
        • Pisal H.
        • Joshi S.
        Reduced folate, increased vitamin B (12) and homocysteine concentrations in women delivering preterm.
        Ann Nutr Metab. 2012; 61: 7-14
        • Wadhwani N.S.
        • Dangat K.D.
        • Joshi A.A.
        • Joshi S.R.
        Maternal micronutrients and omega 3 fatty acids affect placental fatty acid desaturases and transport proteins in Wistar rats.
        Prostaglandins Leukot Essent Fatty Acids. 2013; 88: 235-242
        • Sable P.S.
        • Kale A.A.
        • Joshi S.R.
        Prenatal omega 3 fatty acid supplementation to a micronutrient imbalanced diet protects brain neurotrophins both in the cortex and hippocampus in the adult rat offspring.
        Metabolism. 2013; 62: 1607-1622
        • Carmel R.
        Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiological effects.
        Food Nutr Bull S. 2008; 29: 177-187
        • Bonilla C.
        • Lawlor D.A.
        • Taylor A.E.
        • Gunnell D.J.
        • Ben-Shlomo Y.
        • Ness A.R.
        • et al.
        Vitamin B12 status during pregnancy and child’s IQ at age 8: a Mendelian randomization study in the Avon longitudinal study of parents and children.
        PLoS One. 2012; 7: e51084
        • van de Rest O.
        • van Hooijdonk L.W.
        • Doets E.
        • Schiepers O.J.
        • Eilander A.
        • de Groot L.C.
        B vitamins and n-3 fatty acids for brain development and function: review of human studies.
        Ann Nutr Metab. 2012; 60: 272-292
        • Reeves P.G.
        • Nielsen F.H.
        • Fahey Jr., G.C.
        AIN-93 purified diets for laboratory rodents: final report of the American institute of nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet.
        J Nutr. 1993; 123: 1939-1951
        • Blaise S.A.
        • Nédélec E.
        • Schroeder H.
        • Alberto J.M.
        • Bossenmeyer-Pourié C.
        • Guéant J.L.
        • et al.
        Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats.
        Am J Pathol. 2007; 170: 667-679
        • Manahan-Vaughan D.
        • Schwegler H.
        Strain-dependent variations in spatial learning and in hippocampal synaptic plasticity in the dentate gyrus of freely behaving rats.
        Front Behav Neurosci. 2011; 5: 7
        • Purohit V.
        • Abdelmalek M.F.
        • Barve S.
        • Benevenga N.J.
        • Halsted C.H.
        • Kaplowitz N.
        • et al.
        Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium.
        Am J Clin Nutr. 2007; 86: 14-24
        • Pynn C.J.
        • Henderson N.G.
        • Clark H.
        • Koster G.
        • Bernhard W.
        • Postle A.D.
        Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo.
        J Lipid Res. 2011; 52: 399-407
        • van Wijk N.
        • Watkins C.J.
        • Hageman R.J.
        • Sijben J.
        • Kamphuis P.G.
        • Wurtman R.J.
        • et al.
        Combined dietary folate vitamin B-12 and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats.
        Nutr Metab (Lond). 2012; 9: 49
        • Dangat K.D.
        • Kale A.A.
        • Joshi S.R.
        Maternal supplementation of omega 3 fatty acids to micronutrient-imbalanced diet improves lactation in rat.
        Metabolism. 2011; 60: 1318-1324
        • Amminger G.P.
        • McGorry P.D.
        Update on ω-3 polyunsaturated fatty acids in early-stage psychotic disorders.
        Neuropsychopharmacology. 2012; 37: 309-310
        • Sun H.
        • Yang T.
        • Li Q.
        • Zhu Z.
        • Wang L.
        • Bai G.
        • et al.
        Dexamethasone and vitamin B12 synergistically promote peripheral nerve regeneration in rats by upregulating the expression of brain-derived neurotrophic factor.
        Arch Med Sci. 2012; 8: 924-930
        • Lukiw W.J.
        • Cui J.G.
        • Marcheselli V.L.
        • Bodker M.
        • Botkjaer A.
        • Gotlinger K.
        • et al.
        A role for docosahexaenoic acid-derived neuroprotection D1 in neural cell survival and Alzheimer disease.
        J Clin Invest. 2005; 115: 2774-2783
        • Nieto R.
        • Kukuljan M.
        • Silva H.
        BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory.
        Front Psychiatry. 2013; 4: 45
        • Seifert T.
        • Brassard P.
        • Wissenberg M.
        • Rasmussen P.
        • Nordby P.
        • Stallknecht B.
        • et al.
        Endurance training enhances BDNF release from the human brain.
        Am J Physiol Regul Integr Comp Physiol R. 2010; 298: 372-377
        • Faraji J.
        • Lehmann H.
        • Metz G.A.
        • Sutherland R.J.
        Rats with hippocampal lesion show impaired learning and memory in the ziggurat task: a new task to evaluate spatial behavior.
        Behav Brain Res. 2008; 189: 17-31
        • Hashimoto M.
        • Tanabe Y.
        • Fujii Y.
        • Kikuta T.
        • Shibata H.
        • Shido O.
        Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid-infused rats.
        J Nutr. 2005; 135: 549-555
        • Pérez M.A.
        • Terreros G.
        • Dagnino-Subiabre A.
        Long-term omega-3 fatty acid supplementation induces anti-stress effects and improves learning in rats.
        Behav Brain Funct. 2013; 9: 25
        • de Quervain D.J.
        • Roozendaal B.
        • McGaugh J.L.
        Stress and glucocorticoids impair retrieval of long-term spatial memory.
        Nature. 1998; 394: 787-790
        • Holscher C.
        Stress impairs performance in spatial water maze learning tasks.
        Behav Brain Res. 1999; 100: 225-235
        • Hodges H.
        Maze procedures: the radial-arm and water maze compared.
        Brain Res Cogn Brain Res. 1996; 3: 167-181
        • Cocco S.
        • Diaz G.
        • Stancampiano R.
        • Diana A.
        • Carta M.
        • Curreli R.
        • et al.
        Vitamin A deficiency produces spatial learning and memory impairment in rats.
        Neuroscience. 2002; 115: 475-482
        • Haque A.M.
        • Hashimoto M.
        • Katakura M.
        • Tanabe Y.
        • Hara Y.
        • Shido O.
        Long-term administration of green tea catechins improves spatial cognition learning ability in rats.
        J Nutr. 2006; 136: 1043-1047
        • Osendarp S.J.
        • Baghurst K.I.
        • Bryan J.
        • Calvaresi E.
        • Hughes D.
        • Hussaini M.
        • et al.
        Effect of a 12-mo micronutrient intervention on learning and memory in well-nourished and marginally nourished school-aged children: parallel, randomized, placebo-controlled studies in Australia and Indonesia.
        Am J Clin Nutr. 2007; 86: 1082-1093
        • Muthayya S.
        Maternal nutrition & low birth weight – what is really important?.
        Indian J Med Res. 2009; 130: 600-608