Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review

Santos, Patrícia; Herrmann, Ana P.; Elisabetsky, Elaine; Piato, Angelo

doi:10.1590/1516-4446-2018-0005

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Brazilian Journal of Psychiatry

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Sumário

REVIEW ARTICLE • Braz. J. Psychiatry 41 (02) • Mar-Apr 2019 • https://doi.org/10.1590/1516-4446-2018-0005 copy

Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective:

Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains.

Methods:

The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders.

Results:

The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects.

Conclusion:

Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Anxiety; agomelatine; N-acetylcysteine; omega-3 fatty acids

Compound/dose	Treatment duration	Species	Behavioral tests	Effects	Reference
Agomelatine
2.5-80 mg/kg, i.p.	Acute	Rats	EPM , SI, UV, VCT	Anxiolytic	Millan et al.⁶⁵65. Millan MJ, Brocco M, Gobert A, Dekeyne A. Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl). 2005;177:448-58.
10-75 mg/kg, i.p.	Acute	Rats	Conditioned footshock-induced UV, EPM, VCT,	Anxiolytic	Papp et al.⁶⁶66. Papp M, Litwa E, Gruca P, Mocaër E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol. 2006;17:9-18.
20-40 mg/kg, i.p.Acute	Rats	EPM, NIH, PD, SSWS	Anxiolytic in the EPM	Loiseau et al.⁶⁴64. Loiseau F, Le Bihan C, Hamon M, Thiébot MH. Effects of melatonin and agomelatine in anxiety-related procedures in rats: interaction with diazepam. Eur Neuropsychopharmacol. 2006;16:417-28.
40-50 mg/kg, i.p.	Chronic	Rats	EPM, FST	Prevented prenatal restraint-induced anxiety-like behavior in the EPM	Morley-Fletcher et al.⁵⁸58. Morley-Fletcher S, Mairesse J, Soumier A, Banasr M, Fagioli F, Gabriel C, et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl). 2011;217:301-13.
NAC
50 mg/kg, i.p.,	Acute	Mice	MBB	Inhibited marble-burying behavior	Egashira et al.⁶⁷67. Egashira N, Shirakawa A, Abe M, Niki T, Mishima K, Iwasaki K, et al. N-acetyl-L-cysteine inhibits marble-burying behavior in mice. J Pharmacol Sci. 2012;119:97-101.
150 mg/kg, i.p.	10 days	Rats	EPM, OF, SI	Reversed valproate-induced anxiety-like behavior and social interaction deficit	Chen et al.⁶⁸68. Chen YW, Lin HC, Ng MC, Hsiao YH, Wang CC, Gean PW, et al. Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism. Front Behav Neurosci. 2014;8:219.
30 or 60 mg/kg, i.p.	11 days	Mice	HB, SP	Prevented rhythm disruption-induced anxiety in the HB	Pilz et al.⁶⁹69. Pilz LK, Trojan Y, Quiles CL, Benvenutti R, Melo G, Levandovski R, et al. Effects of N-acetylcysteine and imipramine in a model of acute rhythm disruption in BALB/c mice. Chronobiol Int. 2015;32:248-54.
0.1, 1.0 and 10 mg/L of tank water	Acute	Zebrafish	L/D, NT	Anxiolytic in the L/D, prevented acute stressor-induced anxiety-like behavior in NT	Mocelin et al.⁷⁰70. Mocelin R, Herrmann AP, Marcon M, Rambo CL, Rohden A, Bevilaqua F, et al. N-acetylcysteine prevents stress-induced anxiety behavior in zebrafish. Pharmacol Biochem Behav. 2015;139:121-6.
60-150 mg/kg, i.p.	Acute and subacute (4 days)	Mice	ETM, HB, L/D, OF, SI, SIH	Anxiolytic (except at the elevated T-maze).	Santos et al.⁷¹71. Santos P, Herrmann AP, Benvenutti R, Noetzold G, Giongo F, Gama CS, et al. Anxiolytic properties of N-acetylcysteine in mice. Behav Brain Res. 2017;317:461-9.
Omega-3
Diet supplemented with DHA	Chronic	Mice	OF, L/D, MWM	Anxiolytic in the L/D	Carrié et al.⁷²72. Carrié I, Smirnova M, Clément M, De JD, Francès H, Bourre JM. Docosahexaenoic acid-rich phospholipid supplementation: effect on behavior, learning ability, and retinal function in control and n-3 polyunsaturated fatty acid deficient old mice. Nutr Neurosci. 2002;5:43-52.
Diet supplemented with different combinations of omega-3 PUFA	Chronic	Rats	EPM, OF	Attenuated i.c.v. IL-1 beta-induced anxiety.	Song et al.⁷³73. Song C, Li X, Leonard BE, Horrobin DF. Effects of dietary n-3 or n-6 fatty acids on interleukin-1beta-induced anxiety, stress, and inflammatory responses in rats. J Lipid Res. 2003;44:1984-91.
Diet supplemented with different proportions of ethyl-EPA	Chronic	Rats	EPM, OF	Attenuated the i.c.v. IL-1 beta-induced anxiety	Song et al.⁷⁴74. Song C, Leonard BE, Horrobin DF. Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats. Stress. 2004;7:43-54.
Diet supplemented with EPA + DHA	Chronic	Rats	EPM, modified FST, MWM	Counteracted restraint-induced anxiety	Ferraz et al.⁷⁵75. Ferraz AC, Delattre AM, Almendra RG, Sonagli M, Borges C, Araujo P, et al. Chronic ω-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol. Behav Brain Res. 2011;219:116-22.
Diet supplemented with long-chain omega-3 PUFA	Chronic	Grey mouse lemur (Microcebus murinus)	OF	Anxiolytic	Vinot et al.⁷⁶76. Vinot N, Jouin M, Lhomme-Duchadeuil A, Guesnet P, Alessandri JM, Aujard F, et al. Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate. PloS One. 2011;6:e20491.
Diet supplemented with EPA + DHA	Chronic	Rats	Avoidance conditioning, EPM	Prevented restraint stress-induced anxiety	Pérez et al.⁷⁷77. Pérez MÁ, Terreros G, Dagnino-Subiabre A. Long-term ω-3 fatty acid supplementation induces anti-stress effects and improves learning in rats. Behav Brain Funct. 2013;9:25.
10:1 omega-6/omega-3 diet supplemented with DHA for three generations	Chronic	Mice	EPM, OF	Anxiolytic in third generation male offspring	Jašarević et al.⁷⁸78. Jašarević E, Hecht PM, Fritsche KL, Beversdorf DQ, Geary DC. Dissociable effects of dorsal and ventral hippocampal DHA content on spatial learning and anxiety-like behavior. Neurobiol Learn Mem. 2014;116:59-68.
Diet supplemented with long-chain omega-3 PUFA	Chronic	Grey mouse lemur (Microcebus murinus)	OF, Barnes maze	Anxiolytic	Pifferi et al.⁷⁹79. Pifferi F, Dorieux O, Castellano CA, Croteau E, Masson M, Guillermier M, et al. Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur. J Lipid Res. 2015;56:1511-8.

Compound/disorder	Study design	Study size	Daily dose and treatment duration	Main measures/ instruments	Results	Reference
Agomelatine
GAD	RDBCT	121	25-50 mg, 12 weeks	CGI, HARS, LSEQ, SDS	Anxiolytic	Stein et al.⁸⁰80. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28:561-6.
GAD	Open-label treatment followed by a multicenter RDBCT	477	25-50 mg, 16 weeks (open-label) followed by 26 weeks (RDBCT)	CGI, DESS, HAD, HARS, LSEQ, SDS	Anxiolytic and well-tolerated in long-term treatment. Superior to placebo in preventing relapse.	Stein et al.⁸¹81. Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J Clin Psychiatry. 2012;73:1002-8.
GAD	Multicenter, RDBCT	412	25-50 mg, 12 weeks	CGI, HADS, LSEQ, SDS	Anxiolytic effect similar to escitalopram, with lower adverse events incidence.	Stein et al.⁸²82. Stein DJ, Ahokas A, Márquez MS, Höschl C, Oh KS, Jarema M, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. J Clin Psychiatry. 2014;75:362-8.
GAD	RDBCT	412	10-25 mg, 12 weeks	HARS	Anxiolytic, placebo-agomelatine difference greater with the higher dose.	Stein et al.⁸³83. Stein DJ, Ahokas A, Jarema M, Avedisova AS, Vavrusova L, Chaban O, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: a 12-week, double-blind, placebo-controlled study. Eur Neuropsychopharmacol. 2017;27:526-37.
NAC
TTM	RDBCT	50	1,200-2,400 mg, 12 weeks	CGI, HARS MGH-HPS, PITS	Reduced hair- pulling	Grant et al.⁸⁴84. Durieux AM, Fernandes C, Murphy D, Labouesse MA, Giovanoli S, Meyer U, et al. Targeting glia with N-acetylcysteine modulates brain glutamate and behaviors relevant to neurodevelopmental disorders in C57BL/6J mice. Front Behav Neurosci. 2015;9:343.
OCD (refractory to SRI)	RDBCT	39	Initially 600 mg, doubling weekly to a maximum dose of 2,400 mg (add-on treatment to SRI), 12 weeks	CGI-S, Y-BOCS	Improved mean CGI-S and Y-BOCS scale scores	Afshar et al.⁸⁵85. Afshar H, Roohafza H, Mohammad-Beigi H, Haghighi M, Jahangard L, Shokouh P, et al. N-acetylcysteine add-on treatment in refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2012;32:797-803.
Chronic nail biting	RDBCT	25	800 mg, 2 months	Nail length	Decreased nail biting over the short term	Ghanizadeh et al.⁸⁶86. Ghanizadeh A, Derakhshan N, Berk M. N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial. Antiinflamm Antiallergy Agents Med Chem. 2013;12:223-8.
OCD	RDBCT	44	3,000 mg (add-on treatment), 16 weeks	Y-BOCS	Decreased Y-BOCS score	Sarris et al.⁸⁷87. Sarris J, Oliver G, Camfield DA, Dean OM, Dowling N, Smith DJ, et al. N-acetyl cysteine (nac) in the treatment of obsessive-compulsive disorder: a 16-week, double-blind, randomised, placebo-controlled study. CNS Drugs. 2015;29:801-9.
PTSD and SUD	RDBCT	35	2,400 mg, 8 weeks	CAPS, PCL-M, VAS	Improved PTSD and craving	Back et al.⁸⁸88. Back SE, McCauley JL, Korte KJ, Gros DF, Leavitt V, Gray KM, et al. A double-blind, randomized, controlled pilot trial of N-acetylcysteine in veterans with posttraumatic stress disorder and substance use disorders. J Clin Psychiatry. 2016;77:e1439-e46.
Skin-picking disorder	RDBCT	53	1,200-3,000 mg, 12 weeks	Measures of skin-picking severity: CGI-S and modified Y-BOCS	Decreased skin-picking	Grant et al.⁸⁹89. Grant JE, Chamberlain SR, Redden SA, Leppink EW, Odlaug BL, Kim SW. N-acetylcysteine in the treatment of excoriation disorder: a randomized clinical trial. JAMA Psychiatry. 2016;73:490-6.
OCD	RDBCT	44	2,000 mg (add-on treatment to fluvoxamine), 10 weeks	Y-BOCS	Decreased scores in Y-BOCS	Paydary et al.⁹⁰90. Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016;41:214-9.
Omega-3
Test anxiety	Placebo controlled trial	126	90 mg of α-linolenic acid (omega-3) and 360 mg of linoleic acid (omega-6 fatty acid), 3 weeks	Standardized rating scale	Improved variables associated with test anxiety	Yehuda et al.⁹¹91. Yehuda S, Rabinovitz S, Mostofsky DI. Mixture of essential fatty acids lowers test anxiety. Nutr Neurosci. 2005;8:265-7.
SUD	RDBCT	24	3 g, 3 months	Modified version of the POMS (baseline and monthly)	Decreased anxiety scores progressively	Buydens-Branchey & Branchey⁹²92. Buydens-Branchey L, Branchey M. n-3 polyunsaturated fatty acids decrease anxiety feelings in a population of substance abusers. J Clin Psychopharmacol. 2006;26:661-5.
SUD	RDBCT	22	3 g, 3 months	Modified version of POMS	Decreased anxiety scores	Buydens-Branchey et al.⁹³93. Buydens-Branchey L, Branchey M, Hibbeln JR. Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:568-75.
Healthy young adults	RDBCT	68	2.5 g, 12 weeks	BAI, CES-D	Decreased anxiety	Kiecolt-Glaser et al.⁹⁴94. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Glaser R. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun. 2011;25:1725-34.
Alcoholic patients	RDBCT	31	60 mg EPA + 252 mg DHA, 3 weeks	PSS	Decreased anxiety/stress	Barbadoro et al.⁹⁵95. Barbadoro P, Annino I, Ponzio E, Romanelli RM, D’Errico MM, Prospero E, et al. Fish oil supplementation reduces cortisol basal levels and perceived stress: a randomized, placebo-controlled trial in abstinent alcoholics. Mol Nutr Food Res. 2013;57:1110-4.
Early postmyocardial infarction	RDBCT	52	1 g + standard pharmacotherapy, 1 month	BDI, ESQ, STAI-S, STAI-T, used at the baseline (3rd day of acute myocardial infarction) and after one month	Decreased anxiety (STAI-S)	Haberka et al.⁹⁶96. Haberka M, Mizia-Stec K, Mizia M, Gieszczyk K, Chmiel A, Sitnik-Warchulska K, et al. Effects of n-3 polyunsaturated fatty acids on depressive symptoms, anxiety and emotional state in patients with acute myocardial infarction. Pharmacol Rep. 2013;65:59-68.
PMS	RDBCT	124	2 g, 3 months	VAS	Decreased anxiety severity and duration	Sohrabi et al.⁹⁷97. Sohrabi N, Kashanian M, Ghafoori SS, Malakouti SK. Evaluation of the effect of omega-3 fatty acids in the treatment of premenstrual syndrome: “a pilot trial.” Complement Ther Med. 2013;21:141-6.
Japanese accident survivors (at risk for developing PTSD)	RDBCT	83	1,470 mg DHA + 147 mg EPA, 12 weeks	Monitoring of heart rate and skin conductance, script-driven imagery of their traumatic event	Decreased heart rate	Matsumura et al.⁹⁸98. Matsumura K, Noguchi H, Nishi D, Hamazaki K, Hamazaki T, Matsuoka YJ. Effects of omega-3 polyunsaturated fatty acids on psychophysiological symptoms of posttraumatic stress disorder in accident survivors: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2017;224:27-31.

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[1] Correspondence: Angelo Piato, Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Av. Sarmento Leite, 500, sala 305, CEP 90050-170, Porto Alegre, RS, Brazil. E-mail: angelopiato@ufrgs.br