The Effect of Zinc Supplementation on Circulating Levels of Brain‑Derived Neurotrophic Factor (BDNF): A Systematic Review and Meta‑Analysis of Randomized Controlled Trials

Fahimeh Agh, Motahareh Hasani, Maryam Khazdouz, Fatemehsadat Amiri, Javad Heshmati, Naheed Aryaeian

Abstract


Background: There are randomized controlled trials (RCTs) about the zinc supplementation effect on circulating levels of brain‑derived neurotrophic factor (BDNF). However, the findings of these studies are inconsistent. The purpose of this systematic review and meta‑analysis was to determine the zinc supplementation effect on BDNF and zinc levels in published RCTs. Methods: We searched PubMed/ Medline, Cochrane, Scopus, ISI Web of Science, EMBASE, “Clinicaltrials.gov”, “Cochrane Register of Controlled Trials”, “IRCT” and also key journals up to 2019. RCTs with two intervention (zinc) and control (placebo) groups that evaluated zinc supplementation efficacy on BDNF levels were included. Study heterogeneity was assessed, and then, meta‑analysis was performed using the fixed‑effects model. Results: Four studies were included in the present secondary analysis. Compared with placebo, zinc supplementation significantly enhanced circulating levels of BDNF [(SMD): 0.31, 95% confidence interval (CI): (0.22, 0.61)] and zinc [(SMD): 0.88, 95% CI: (0.54, 1.22)] with no considerable heterogeneity among the studies [(Q = 3.46; P = 0.32; I2% = 13.4); (Q = 2.01; P = 0, 37; I2% = 0.5), respectively]. Conclusions: Our results propose that zinc supplementation can increase the circulating levels of BDNF and zinc. This study was registered at PROSPERO as CRD42020149513.

Keywords


Brain‑derived neurotrophic factor; meta‑analysis; randomized controlled trial; systematic review; zinc

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References


Erkkinen MG, Kim MO, Geschwind MD. Clinical neurology

and epidemiology of the major neurodegenerative diseases. Cold

Spring Harb Perspect Biol 2018;10:a033118.

World Population Ageing 2017 Highlights: The United Nations.

Zuccato C, Cattaneo E. Brain‑derived neurotrophic factor in

neurodegenerative diseases. Nat Rev Neurol 2009;5:311‑22.

Wang ZH, Wu W, Kang SS, Liu X, Wu Z, Peng J, et al. BDNF

inhibits neurodegenerative disease–associated asparaginyl

endopeptidase activity via phosphorylation by AKT. JCI Insight

;3:e99007. doi: 10.1172/jci.insight. 99007.

Giacobbo BL, Doorduin J, Klein HC, Dierckx RA, Bromberg E,

de Vries EF. Brain‑derived neurotrophic factor in brain disorders:

Focus on neuroinflammation. Mol Neurobiol 2019;56:3295‑312.

Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M,

Thadani A, et al. A BDNF autocrine loop in adult sensory

neurons prevents cell death. Nature 1995;374:450‑3.

Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW,

Bora SH, et al. Brain‑derived neurotrophic factor‑deficient mice

develop aggressiveness and hyperphagia in conjunction with

brain serotonergic abnormalities. Proc Natl Acad Sci U S A

;96:15239‑44.

Han R, Liu Z, Sun N, Liu S, Li L, Shen Y, et al. BDNF alleviates

neuroinflammation in the hippocampus of type 1 diabetic mice

via blocking the aberrant HMGB1/RAGE/NF‑κB pathway.

Aging Dis 2019;10:611‑25.

Kang H, Schuman EM. Long‑lasting neurotrophin‑induced

enhancement of synaptic transmission in the adult hippocampus.

Science 1995;267:1658‑62.

Zigova T, Pencea V, Wiegand SJ, Luskin MB. Intraventricular

administration of BDNF increases the number of newly

generated neurons in the adult olfactory bulb. Mol Cell Neurosci

;11:234‑45.

Lee J, Duan W, Mattson MP. Evidence that brain-derived

neurotrophic factor is required for basal neurogenesis and

mediates, in part, the enhancement of neurogenesis by dietary

restriction in the hippocampus of adult mice. J Neurochem

;82:1367‑75.

Jiang Y, Wei N, Zhu J, Lu T, Chen Z, Xu G, et al. Effects of

brain‑derived neurotrophic factor on local inflammation in

experimental stroke of rat. Mediators Inflamm 2010;2010:372423.

doi: 10.1155/2010/372423.

Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA,

Winslow JW. BDNF mRNA is decreased in the hippocampus of

individuals with Alzheimer’s disease. Neuron 1991;7:695‑702.

Howells D, Porritt MJ, Wong J, Batchelor P, Kalnins R,

Hughes A, et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol

;166:127‑35.

Ventriglia M, Zanardini R, Bonomini C, Zanetti O, Volpe D,

Pasqualetti P, et al. Serum brain‑derived neurotrophic factor

levels in different neurological diseases. BioMed Res Int

;2013:901082. doi: 10.1155/2013/901082.

Văcăraş V, Major ZZ, Buzoianu AD. Brain‑derived neurotrophic

factor levels under chronic natalizumab treatment in multiple

sclerosis. A preliminary report. Neurol Neurochir Pol 2017;51:221‑6.

Nishio T, Sunohara N, Furukawa S. Neutrophin switching in spinal

motoneurons of amyotrophic lateral sclerosis. Neuroreport 1998;9:1661‑5.

Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT.

Increased hippocampal BDNF immunoreactivity in subjects treated

with antidepressant medication. Biol Psychiatry 2001;50:260‑5.

Rendeiro C, Vauzour D, Rattray M, Waffo‑Téguo P, Mérillon

JM, Butler LT, et al. Dietary levels of pure flavonoids improve

spatial memory performance and increase hippocampal

brain‑derived neurotrophic factor. PloS One 2013;8:e63535. doi:

1371/journal.pone. 0063535.

Marinus N, Hansen D, Feys P, Meesen R, Timmermans A,

Spildooren J. The Impact of different types of exercise training on

peripheral blood brain‑derived neurotrophic factor concentrations

in older adults: A meta‑analysis. Sports Med 2019;49:1529‑46.

Pawełczyk T, Grancow‑Grabka M, Trafalska E, Szemraj J,

Żurner N, Pawełczyk A. An increase in plasma brain derived

neurotrophic factor levels is related to n‑3 polyunsaturated

fatty acid efficacy in first episode schizophrenia: Secondary

outcome analysis of the OFFER randomized clinical trial.

Psychopharmacology 2019;236:2811‑22.

Wiciński M, Malinowski B, Węclewicz MM, Grześk E,

Grześk G. Resveratrol increases serum BDNF concentrations

and reduces vascular smooth muscle cells contractility

via a NOS‑3‑independent mechanism. Biomed Res Int

;2017:9202954. doi: 10.1155/2017/9202954.

Jafari F, Amani R, Tarrahi MJ. Effect of zinc supplementation

on physical and psychological symptoms, biomarkers of

inflammation, oxidative stress, and brain‑derived neurotrophic

factor in young women with premenstrual syndrome:

A randomized, double‑blind, placebo‑controlled trial. Biol Trace

Elem Res 2020;194:89‑95.

Prakash A, Bharti K, Majeed ABA. Zinc: Indications in brain

disorders. Fundam Clin Pharmacol 2015;29:131‑49.

Mariani E, Mangialasche F, Feliziani F, Cecchetti R,

Malavolta M, Bastiani P, et al. Effects of zinc supplementation

on antioxidant enzyme activities in healthy old subjects. Exp

Gerontol 2008;43:445‑51.

Mousavi SM, Djafarian K, Mojtahed A, Varkaneh HK, Shab‑Bidar S.

The effect of zinc supplementation on plasma C‑reactive protein

concentrations: A systematic review and meta‑analysis of randomized

controlled trials. Eur J Pharmacol 2018;834:10‑6.

Travaglia A, La Mendola D, Magrì A, Pietropaolo A, Nicoletti VG,

Grasso G, et al. Zinc (II) interactions with brain‑derived

neurotrophic factor N‑terminal peptide fragments: Inorganic features

and biological perspectives. Inorg Chem 2013;52:11075‑83.

Cochrane risk of bias tool for randomized controlled trials.

Available from: Ncbi.nlm.nih.gov NBK115843 bin appe‑fm2.

DerSimonian R, Laird N. Meta‑analysis in clinical trials. Control

Clin Trials 1986;7:177‑88.

Whitehead A, Whitehead J. A general parametric approach

to the meta-analysis of randomized clinical trials. Stat Med

;10:1665‑77.

Solati Z, Jazayeri S, Tehrani‑Doost M, Mahmoodianfard S,

Gohari MR. Zinc monotherapy increases serum brain‑derived

neurotrophic factor (BDNF) levels and decreases depressive

symptoms in overweight or obese subjects: A double‑blind,

randomized, placebo‑controlled trial. Nutr Neurosci 2015;18:162‑8.

Kheirouri S, Naghizadeh S, Alizadeh M. Zinc supplementation

does not influence serum levels of VEGF, BDNF, and NGF in

diabetic retinopathy patients: A randomized controlled clinical

trial. Nutr Neurosci 2019;22:718‑24.

Ranjbar E, Shams J, Sabetkasaei M, M‑Shirazi M, Rashidkhani B,

Mostafavi A, et al. Effects of zinc supplementation on efficacy of

antidepressant therapy, inflammatory cytokines, and brain‑derived

neurotrophic factor in patients with major depression. Nutr

Neurosci 2014;17:65‑71.

Toh YL, Ng T, Tan M, Tan A, Chan A. Impact of brain-derived

neurotrophic factor genetic polymorphism on cognition: A systematic

review. Brain Behav 2018;8:e01009. doi: 10.1002/brb3.1009.

Fernandes BS, Molendijk ML, Köhler CA, Soares JC,

Leite CMG, Machado‑Vieira R, et al. Peripheral brain‑derived

neurotrophic factor (BDNF) as a biomarker in bipolar disorder:

A meta‑analysis of 52 studies. BMC Med 2015;13:289.

Salas-Magaña M, Tovilla-Zárate CA, González-Castro TB, JuárezRojop IE, López-Narváez ML, Rodríguez-Pérez JM, et al. Decrease

in brain-derived neurotrophic factor at plasma level but not in serum

concentrations in suicide behavior: A systematic review and metaanalysis. Brain Behav 2017;7:e00706. doi: 10.1002/brb3.706.

Ng TKS, Ho CSH, Tam WWS, Kua EH, Ho RC‑M. Decreased

serum brain‑derived neurotrophic factor (BDNF) levels in

patients with alzheimer’s disease (AD): A systematic review and

meta‑analysis. Int J Mol Sci 2019;20:257.

Rahmani F, Saghazadeh A, Rahmani M, Teixeira AL, Rezaei N,

Aghamollaii V, et al. Plasma levels of brain‑derived neurotrophic

factor in patients with Parkinson disease: A systematic review

and meta‑analysis. Brain Res 2019;1704:127‑36.

Toll A, Mané A. Brain‑derived neurotrophic factor levels in first episode

of psychosis: A systematic review. World J Psychiatry 2015;5:154‑9.

Cui H, Jin Y, Wang J, Weng X, Li C. Serum brain‑derived

neurotrophic factor (BDNF) levels in schizophrenia: A systematic

review. Shanghai Arch Psychiatry 2012;24:250‑61.

Bora E. Peripheral inflammatory and neurotrophic biomarkers of

cognitive impairment in schizophrenia: A meta‑analysis. Psychol

Med 2019;49:1971‑9.

Szuhany KL, Bugatti M, Otto MW. A meta‑analytic review of

the effects of exercise on brain‑derived neurotrophic factor.

J Psychiatr Res 2015;60:56‑64.

Neshatdoust S, Saunders C, Castle SM, Vauzour D, Williams C,

Butler L, et al. High‑flavonoid intake induces cognitive

improvements linked to changes in serum brain‑derived

neurotrophic factor: Two randomised, controlled trials. Nutr

Healthy Aging 2016;4:81‑93.

Sechi S, Chiavolelli F, Spissu N, Di Cerbo A, Canello S, Guidetti G,

et al. An antioxidant dietary supplement improves brain‑derived

neurotrophic factor levels in serum of aged dogs: Preliminary

results. J Vet Med 2015;2015:412501. doi: 10.1155/2015/412501.

Corona C, Masciopinto F, Silvestri E, Viscovo AD, Lattanzio R,

Sorda RL, et al. Dietary zinc supplementation of 3xTg‑AD mice

increases BDNF levels and prevents cognitive deficits as well

as mitochondrial dysfunction. Cell Death Dis 2010;1:e91. doi:

1038/cddis. 2010.73.

Huang YZ, Pan E, Xiong Z‑Q, McNamara JO. Zinc‑mediated

transactivation of TrkB potentiates the hippocampal mossy

fiber‑CA3 pyramid synapse. Neuron 2008;57:546‑58.

McMurphy T, Huang W, Liu X, Siu JJ, Queen NJ, Xiao R, et al.

Hypothalamic gene transfer of BDNF promotes healthy aging in

mice. Aging Cell 2019;18:e12846.