Abstract
Anxiety Disorders and Posttraumatic Stress Disorders (PTSD) associated with type-1 diabetes mellitus (T1DM) are increasingly common comorbidities and the treatment is quite challenging. In that sense, evidence indicates that the anticonvulsant pregabalin is highly effective in treating severe cases of anxiety, as well as PTSD and diabetic neuropathic pain which is also very prevalent in T1DM. Herein, the short- and long-term effects of a single injection of pregabalin on the acquisition of a fear extinction memory and parameters of anxiety in induced-T1DM animals were investigated. For that, we used the contextual fear conditioning (CFC) and elevated plus maze paradigms, respectively. A putative antioxidant activity was also evaluated. Our findings demonstrated that induced-T1DM animals presented greater expression of fear memory, difficulty in extinguishing this fear memory, associated with a more pronounced anxiety-like response. Pregabalin was able to induce a short and long-lasting effect by facilitating the acquisition of the fear extinction memory and inducing a later anxiolytic-like effect. Also, the increased lipid peroxidation levels in the hippocampus and prefrontal cortex of induced-T1DM rats were reduced after pregabalin injection, while the decreased levels of reduced glutathione were increased in the hippocampus. Despite the need for more studies to understand the mechanism of action of pregabalin under these conditions, our data demonstrate for the first time that a single injection of pregabalin in a specific time window was able to improve behavioral parameters in addition to inducing neuroprotective effect. Thus, pregabalin has potential worth exploring for the treatment of PTSD and/or Anxiety associated with T1DM.
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References
Ahmed A, Zeng G, Jiang D et al (2019) Time-dependent impairments in learning and memory in Streptozotocin-induced hyperglycemic rats. Metab Brain Dis 34:1431–1446. https://doi.org/10.1007/s11011-019-00448-7
Aldemir E, Altintoprak AE, Coşkunol H (2015) Pregabalin dependence: A case report. Turk Psikiyatr Derg 26:217–220. https://doi.org/10.2174/1574886309666141022101956
Ali SA, Zaitone SA, Dessouki AA, Ali AA (2019) Pregabalin affords retinal neuroprotection in diabetic rats: Suppression of retinal glutamate, microglia cell expression and apoptotic cell death. Exp Eye Res 184:78–90. https://doi.org/10.1016/j.exer.2019.04.014
Anwer T, Sharma M, Pillai KK, Khan G (2012) Protective effect of Withania somnifera against oxidative stress and pancreatic β-cell damage in type 2 diabetic rats. Acta Pol Pharm - Drug Res 69:1095–1101
Asci H, Ozmen O, Erzurumlu Y, Savas HB, Temel EN, Icten P, Hasseyid N (2020) Ameliorative effects of pregabalin on LPS induced endothelial and cardiac toxicity. Biotech Histochem. https://doi.org/10.1080/10520295.2020.1810315
Aslankoc R, Savran M, Ozmen O, Asci S (2018) Hippocampus and cerebellum damage in sepsis induced by lipopolysaccharide in aged rats - Pregabalin can prevent damage. Biomed Pharmacother 108:1384–1392. https://doi.org/10.1016/j.biopha.2018.09.162
Asok A, Kandel ER, Rayman JB (2019) The neurobiology of fear generalization. Front Behav Neurosci 12:329. https://doi.org/10.3389/fnbeh.2018.00329
Aswar U, Chepurwar S, Shintre S, Aswar M (2017) Telmisartan attenuates diabetes induced depression in rats. Pharmacol Reports 69:358–364. https://doi.org/10.1016/j.pharep.2016.12.004
Auxéméry, (2012) Posttraumatic stress disorder (PTSD) as a consequence of the interaction between an individual genetic susceptibility, a traumatogenic event and a social context]. Encephale 38:373–380
Baldwin DS, Den Boer JA, Lyndon G et al (2015) Efficacy and safety of pregabalin in generalised anxiety disorder: A critical review of the literature. J Psychopharmacol 29:1047–1060. https://doi.org/10.1177/0269881115598411
Banagozar Mohammadi A, Torbati M, Farajdokht F et al (2019) Sericin alleviates restraint stress induced depressive- and anxiety-like behaviors via modulation of oxidative stress, neuroinflammation and apoptosis in the prefrontal cortex and hippocampus. Brain Res 1715:47–56. https://doi.org/10.1016/j.brainres.2019.03.020
Baniasadi M, Hosseini G, Bordbar MRF et al (2014) Effect of pregabalin augmentation in treatment of patients with combat-related chronic posttraumatic stress disorder: A randomized controlled trial. J Psychiatr Pract 20:419–427. https://doi.org/10.1097/01.pra.0000456590.12998.41
Barclay J, Balaguero N, Mione M et al (2001) Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J Neurosci 21:6095–6104. https://doi.org/10.1523/jneurosci.21-16-06095.2001
Bludau S, Bzdok D, Gruber O et al (2016) Medial prefrontal aberrations in major depressive disorder revealed by cytoarchitectonically informed voxel-based morphometry. Am J Psychiatry 173:291–298. https://doi.org/10.1176/appi.ajp.2015.15030349
Blum RA, Comstock TJ, Sica DA et al (1994) Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 56:154–159. https://doi.org/10.1038/clpt.1994.118
Bockbrader HN, Wesche D, Miller R et al (2010) A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 49:661–669. https://doi.org/10.2165/11536200-000000000-00000
Bremner JD, Randall P, Scott TM et al (1995) MRI-based measurement of hippocampal volume in patients with combat- related posttraumatic stress disorder. Am J Psychiatry 152:973–981. https://doi.org/10.1176/ajp.152.7.973
Buchberger B, Huppertz H, Krabbe L et al (2016) Symptoms of depression and anxiety in youth with type 1 diabetes: A systematic review and meta-analysis. Psychoneuroendocrinology 70:70–84. https://doi.org/10.1016/j.psyneuen.2016.04.019
Buoli M, Caldiroli A, Serati M (2017) Pharmacokinetic evaluation of pregabalin for the treatment of generalized anxiety disorder. Expert Opin Drug Metab Toxicol 13:351–359. https://doi.org/10.1080/17425255.2017.1281247
Chaves YC, Genaro K, Stern CA et al (2020) Two-weeks treatment with cannabidiol improves biophysical and behavioral deficits associated with experimental type-1 diabetes. Neurosci Lett 729:135020. https://doi.org/10.1016/j.neulet.2020.135020
Chincholkar M (2020) Gabapentinoids: pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br J Pain 14:104–114. https://doi.org/10.1177/2049463720912496
Cole RL, Lechner SM, Williams ME, Prodanovich P, Bleicher L, Varney MA, Gu G (2005) Differential distribution of voltage-gated calcium channel alpha-2 delta (alpha2delta) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia. J Comp Neurol 491(3):246–269. https://doi.org/10.1002/cne.20693
Cruz APM, Frei F, Graeff FG (1994) Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 49:171–176. https://doi.org/10.1016/0091-3057(94)90472-3
de la Cruz-Álvarez LE, Zúñiga-Romero Á, Huerta-Cruz JC et al (2018) Antiallodynic interaction and motor performance of the pregabalin/thioctic acid and pregabalin/α-tocopherol combinations in neonatal streptozotocin-induced diabetic rats. Drug Dev Res 79:362–369. https://doi.org/10.1002/ddr.21473
da Silva Dias IC, Carabelli B, Ishii DK et al (2016) Indoleamine-2,3-Dioxygenase/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes. Mol Neurobiol 53:6997–7009. https://doi.org/10.1007/s12035-015-9617-0
de Morais H, de Souza CP, da Silva LM et al (2014) Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocin-diabetic rats. Behav Brain Res 258:52–64. https://doi.org/10.1016/j.bbr.2013.10.011
de Souza CP, Gambeta E, Stern CAJ, Zanoveli JM (2019) Posttraumatic stress disorder-type behaviors in streptozotocin-induced diabetic rats can be prevented by prolonged treatment with vitamin E. Behav Brain Res 359:749–754. https://doi.org/10.1016/j.bbr.2018.09.008
Diz-Chaves Y, Gil-Lozano M, Toba L, Fandiño J, Ogando H, González-Matías LC, Mallo F (2016) Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis. J Endocrinol 230(2):R77–R94. https://doi.org/10.1530/JOE-16-0118
Demir CF, Balduz M, Taşcı İ, Kuloğlu T (2021) Protective effect of pregabalin on the brain tissue of diabetic rats. Diabetol Int 12:207–216. https://doi.org/10.1007/s13340-020-00476-0
Dobrea C, Buoli M, Arici C et al (2012) Tolerability and use in co-administration of pregabalin in affective patients: A 6-month prospective naturalistic study. Expert Opin Drug Saf 11:893–899. https://doi.org/10.1517/14740338.2012.720971
dos Santos MAB, Ceretta LB, Réus GZ et al (2014) Anxiety disorders are associated with quality of life impairment in patients with insulin-dependent type 2 diabetes: A case-control study. Rev Bras Psiquiatr 36:298–304. https://doi.org/10.1590/1516-4446-2013-1230
Field MJ, Oles RJ, Singh L (2001) Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity. Br J Pharmacol 132:1–4. https://doi.org/10.1038/sj.bjp.0703794
Finnerup NB, Attal N, Haroutounian S et al (2015) Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol 14:162–173. https://doi.org/10.1016/S1474-4422(14)70251-0
Fowler M, Garza TH, Slater TM et al (2012) The relationship between gabapentin and pregabalin and posttraumatic stress disorder in burned servicemembers. J Burn Care Res 33:612–618. https://doi.org/10.1097/BCR.0b013e31823dc710
Frampton JE (2014) Pregabalin: A review of its use in adults with generalized anxiety disorder. CNS Drugs 28:835–854. https://doi.org/10.1007/s40263-014-0192-0
Gahr M, Franke B, Freudenmann RW et al (2013) Concerns about pregabalin: Further experience with its potential of causing addictive behaviors. J Addict Med 7:147–149. https://doi.org/10.1097/ADM.0b013e3182872718
Gambeta E, de Souza CP, de Morais H, Zanoveli JM (2016) Reestablishment of the hyperglycemia to the normal levels seems not to be essential to the anxiolytic-like effect induced by insulin. Metab Brain Dis 31:563–571. https://doi.org/10.1007/s11011-015-9770-1
Garakani A, Murrough JW, Freire RC, et al (2020) Pharmacotherapy of anxiety disorders: current and emerging treatment options. Front Psychiatry 11:595584. https://doi.org/10.3389/fpsyt.2020.595584
Greenblatt HK, Greenblatt DJ (2018) Gabapentin and Pregabalin for the Treatment of Anxiety Disorders. Clin Pharmacol Drug Dev 7:228–232. https://doi.org/10.1002/cpdd.446
Grosshans M, Mutschler J, Hermann D et al (2010) Pregabalin abuse, dependence, and withdrawal: A case report. Am J Psychiatry 167:869. https://doi.org/10.1176/appi.ajp.2010.09091269
Gupta D, Radhakrishnan M, Kurhe Y (2014) Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice. Metab Brain Dis 29:737–746. https://doi.org/10.1007/s11011-014-9540-5
Gupta D, Radhakrishnan M, Kurhe Y (2015) Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice. Steroids 96:95–102. https://doi.org/10.1016/j.steroids.2015.01.021
Ikeda H, Ikegami M, Kai M, Kamei J (2015) Cannabinoid functions in the amygdala contribute to conditioned fear memory in streptozotocin-induced diabetic mice: Interaction with glutamatergic functions. Exp Neurol 269:233–241. https://doi.org/10.1016/j.expneurol.2015.04.012
Ikeda H, Yamamoto S, Kamei J (2021) Increase in brain l-lactate enhances fear memory in diabetic mice: Involvement of glutamate neurons. Brain Res 1767:147560. https://doi.org/10.1016/j.brainres.2021.147560
Jacobson AM, Ryan CM, Cleary PA et al (2011) Biomedical risk factors for decreased cognitive functioning in type 1 diabetes: An 18 year follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. Diabetologia 54:245–255. https://doi.org/10.1007/s00125-010-1883-9
Jiang ZY, Woollard ACS, Wolff SP (1991) Lipid hydroperoxide measurement by oxidation of Fe2+ in the presence of xylenol orange. Comparison with the TBA assay and an iodometric method. Lipids 26:853–856. https://doi.org/10.1007/BF02536169
Kanazawa LKS, Vecchia DD, Wendler EM et al (2016) Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice. Free Radic Biol Med 99:79–86. https://doi.org/10.1016/j.freeradbiomed.2016.07.027
Korte SM, De Boer SF (2003) A robust animal model of state anxiety: Fear-potentiated behaviour in the elevated plus-maze. Eur J Pharmacol 463:163–175. https://doi.org/10.1016/S0014-2999(03)01279-2
Kuznetsova NV, Pal’chikova NA, Kuzminova OI, Selyatitskaya VG (2014) Production of corticosteroid hormones in vitro by adrenals in rats with streptozotocin-induced diabetes. Bull Exp Biol Med 157(1):28–31. https://doi.org/10.1007/s10517-014-2484-2
La Porta C, Lara-Mayorga IM, Negrete R, Maldonado R (2016) Effects of pregabalin on the nociceptive, emotional and cognitive manifestations of neuropathic pain in mice. Eur J Pain 20(9):1454–66. https://doi.org/10.1002/ejp.868
Li Z, Taylor CP, Weber M et al (2011) Pregabalin is a potent and selective ligand for α 2δ- 1 and α 2δ-2 calcium channel subunits. Eur J Pharmacol 667:80–90. https://doi.org/10.1016/j.ejphar.2011.05.054
Lustman PJ, Clouse RE (2005) Depression in diabetic patients: The relationship between mood and glycemic control. J Diabetes Complications 19:113–122. https://doi.org/10.1016/j.jdiacomp.2004.01.002
MacQueen GM, Campbell S, McEwen BS et al (2005) Course of Illness, Hippocampal Function, and Hippocampal Volume in Major Depression. Focus (Madison) 3:146–155. https://doi.org/10.1176/foc.3.1.146
Mann D, Liu J, Chew ML et al (2014) Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: A phase 1, randomized controlled study. Epilepsia 55:1934–1943. https://doi.org/10.1111/epi.12830
Matsunaga Y, Negishi T, Hatakeyama A et al (2016) Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats. Int J Dev Neurosci 53:58–67. https://doi.org/10.1016/j.ijdevneu.2016.07.004
Mishra T, Das AP, Sen A (2012) Phytochemical Screening and ln-vitro Antioxidant Profiling of Solvent Fractions of Canna edulis Ker Gawler. Free Radicals Antioxidants 2:13–20. https://doi.org/10.5530/ax.2012.2.5
Moulton CD, Pickup JC, Ismail K (2015) The link between depression and diabetes: The search for shared mechanisms. Lancet Diabetes Endocrinol 3:461–471. https://doi.org/10.1016/S2213-8587(15)00134-5
Muriach M, Flores-Bellver M, Romero FJ, Barcia JM (2014) Diabetes and the brain: Oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev 2014. https://doi.org/10.1155/2014/102158
Onakpoya IJ, Thomas ET, Lee JJ et al (2019) Benefits and harms of pregabalin in the management of neuropathic pain: A rapid review and meta-analysis of randomised clinical trials. BMJ Open 9. https://doi.org/10.1136/bmjopen-2018-023600
Pande AC, Crockatt JG, Feltner DE et al (2003) Pregabalin in generalized anxiety disorder: A placebo-controlled trial. Am J Psychiatry 160:533–540. https://doi.org/10.1176/appi.ajp.160.3.533
Patel R, Dickenson AH (2016) Mechanisms of the gabapentinoids and α2δ-1 calcium channel subunit in neuropathic pain. Pharmacol Res Perspect 4(2):e00205. https://doi.org/10.1002/prp2.205
Pereira MM, de Morais H, dos Santos SE et al (2018) The antioxidant gallic acid induces anxiolytic-, but not antidepressant-like effect, in streptozotocin-induced diabetes. Metab Brain Dis 33:1573–1584. https://doi.org/10.1007/s11011-018-0264-9
Pitocco D, Zaccardi F, Di Stasio E et al (2010) Oxidative stress, nitric oxide, and diabetes. Rev Diabet Stud 7:15–25. https://doi.org/10.1900/RDS.2010.7.15
Pohl RB, Feltner DE, Fieve RR, Pande AC (2005) Efficacy of pregabalin in the treatment of generalized anxiety disorder: Double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol 25:151–158. https://doi.org/10.1097/01.jcp.0000155820.74832.b0
Prabhakar V, Gupta D, Kanade P, Radhakrishnan M (2015) Diabetes-associated depression: The serotonergic system as a novel multifunctional target. Indian J Pharmacol 47:4–10. https://doi.org/10.4103/0253-7613.150305
Rajput R, Gehlawat P, Gehlan D et al (2016) Prevalence and predictors of depression and anxiety in patients of diabetes mellitus in a tertiary care center. Indian J Endocrinol Metab 20:746–751. https://doi.org/10.4103/2230-8210.192924
Rebolledo-Solleiro D, Araiza LFO, Broccoli L et al (2016) Dopamine D1 receptor activity is involved in the increased anxiety levels observed in STZ-induced diabetes in rats. Behav Brain Res 313:293–301. https://doi.org/10.1016/j.bbr.2016.06.060
Renna CP, Boyer BA, Prout MF, Scheiner G (2016) Posttraumatic Stress Related to Hyperglycemia: Prevalence in Adults with Type I Diabetes. J Clin Psychol Med Settings 23:269–284. https://doi.org/10.1007/s10880-016-9463-x
Réus GZ, Carlessi AS, Silva RH et al (2019) Relationship of oxidative stress as a link between diabetes mellitus and major depressive disorder. Oxid Med Cell Longev 2019:8637970. https://doi.org/10.1155/2019/8637970
Ribeiro TO, Bueno-de-Camargo LM, Waltrick APF et al (2020) Activation of mineralocorticoid receptors facilitate the acquisition of fear memory extinction and impair the generalization of fear memory in diabetic animals. Psychopharmacology 237:529–542. https://doi.org/10.1007/s00213-019-05388-9
Rickels K, Pollack MH, Feltner DE et al (2005) Pregabalin for treatment of generalized anxiety disorder: A 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry 62:1022–1030. https://doi.org/10.1001/archpsyc.62.9.1022
Robert Lee Page II, Cantu M, Lindenfeld J et al (2008) Possible heart failure exacerbation associated with pregabalin: Case discussion and literature review. J Cardiovasc Med 9:922–925. https://doi.org/10.2459/JCM.0b013e3282fb7629
Sałat K, Gdula-Argasińska J, Malikowska N et al (2016) Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice. Naunyn Schmiedebergs Arch Pharmacol 389:613–623. https://doi.org/10.1007/s00210-016-1230-x
Sałat K, Podkowa A, Malikowska N, Trajer J (2017) Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia. Toxicol Mech Methods 27(3):181–190. https://doi.org/10.1080/15376516.2016.1273426
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205. https://doi.org/10.1016/0003-2697(68)90092-4
Sharma M, Gupta S, Singh K et al (2016) Association of glutathione-S-transferase with patients of type 2 diabetes mellitus with and without nephropathy. Diabetes Metab Syndr Clin Res Rev 10:194–197. https://doi.org/10.1016/j.dsx.2016.06.006
Siba IP, Bortolanza M, Frazão Vital MAB et al (2017) Fish oil prevents rodent anxious states comorbid with diabetes: A putative involvement of nitric oxide modulation. Behav Brain Res 326:173–186. https://doi.org/10.1016/j.bbr.2017.03.008
Silva RCB, Brandão ML (2000) Acute and chronic effects of gepirone and fluoxetine in rats tested in the elevated plus-maze: An ethological analysis. Pharmacol Biochem Behav 65:209–216. https://doi.org/10.1016/S0091-3057(99)00193-8
Taylor CP, Angelotti T, Fauman E (2007) Pharmacology and mechanism of action of pregabalin: The calcium channel α2-δ (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73:137–150. https://doi.org/10.1016/j.eplepsyres.2006.09.008
Takahashi Y, Nishimura T, Higuchi K et al (2018) Transport of pregabalin via L-type amino acid transporter 1 (SLC7A5) in human brain capillary endothelial cell line. Pharm Res 35(12):246. https://doi.org/10.1007/s11095-018-2532-0
Tesfaye S, Wilhelm S, Lledo A et al (2013) Duloxetine and pregabalin: High-dose monotherapy or their combination? the “cOMBO-DN study” - A multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 154(12):2616–2625. https://doi.org/10.1016/j.pain.2013.05.043
Vaccarino V, Goldberg J, Magruder KM et al (2014) Posttraumatic stress disorder and incidence of type-2 diabetes: Aprospective twin study. J Psychiatr Res 56:158–164. https://doi.org/10.1016/j.jpsychires.2014.05.019
Valdivieso DA, Baughan TG, Canavati UM et al (2018) Effects of pregabalin on neurobehavior in an adult male rat model of PTSD. PLoS One 13(12):e0209494. https://doi.org/10.1371/journal.pone.0209494
Venturini CD, Merlo S, Souto AA et al (2010) Resveratrol and red wine function as antioxidants in the central nervous system without cellular proliferative effects during experimental diabetes. Oxid Med Cell Longev 3(6):434–41. https://doi.org/10.4161/oxim.3.6.14741
Wang XP, Ye P, Lv J et al (2019) Expression Changes of NMDA and AMPA Receptor Subunits in the Hippocampus in rats with Diabetes Induced by Streptozotocin Coupled with Memory Impairment. Neurochem Res 44:978–993. https://doi.org/10.1007/s11064-019-02733-4
Weisberg RB, Bruce SE, Machan JT (2002) Nonpsychiatric illness among primary care patients with trauma histories and posttraumatic stress disorder. Prim Care Companion J Clin Psychiatry 4:118
Yamamoto S, Takahashi Y, Kato F (2021) Input-dependent synaptic suppression by pregabalin in the central amygdala in male mice with inflammatory pain. Neurobiol Pain 10:100078. https://doi.org/10.1016/j.ynpai.2021.100078
Zanoveli JM, Morais Hd, Dias IC, et al (2016) Depression associated with diabetes: From pathophysiology to treatment. Curr Diabetes Rev 12(3):165–78. https://doi.org/10.2174/1573399811666150515125349
Zohar J, Matar MA, Ifergane G et al (2008) Brief post-stressor treatment with pregabalin in an animal model for PTSD: Short-term anxiolytic effects without long-term anxiogenic effect. Eur Neuropsychopharmacol 18:653–666. https://doi.org/10.1016/j.euroneuro.2008.04.009
Zung A, Blumenfeld O, Shehadeh N et al (2012) Increase in the incidence of type 1 diabetes in Israeli children following the Second Lebanon War. Pediatr Diabetes 13:326–333. https://doi.org/10.1111/j.1399-5448.2011.00838.x
Chen F-A, Wu A-B, Chen C-Y (2004) The influence of different treatments on the free radical scavenging activity of burdock and variations of its active components. Food Chem 86(4):479–484. 10.1016/j.foodchem.2003.09.02.
Acknowledgements
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES—Finance Code 001) and Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNP). AHB de Lima Silva and DRRadulski are recipients of CAPES fellowships.
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This study was supported by Brazilian grants from Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq; 303863/2020–0), which had no other role in the design of the study, collection and analysis of data, and decision to submit the paper for publication. JMZ is a recipient of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil – 1A).
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Janaina Menezes Zanoveli, Alvaro Henrique Bernardo de Lima Silva, Debora Rasec Radulski, Gabriela Saidel Pereira and Alexandra Acco. The first draft of the manuscript was written by Alvaro Henrique Bernardo de Lima Silva and Janaina Menezes Zanoveli and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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de Lima Silva, A.H.B., Radulski, D.R., Pereira, G.S. et al. A single injection of pregabalin induces short- and long-term beneficial effects on fear memory and anxiety-like behavior in rats with experimental type-1 diabetes mellitus. Metab Brain Dis 37, 1095–1110 (2022). https://doi.org/10.1007/s11011-022-00936-3
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DOI: https://doi.org/10.1007/s11011-022-00936-3