Abscisic acid interplays with PPARγ receptors and ameliorates diabetes-induced cognitive deficits in rats

Document Type : Original Research Article

Authors

1 Department of Biology, Faculty of Sciences, Lorestan University, Khorramabad, Iran

2 Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

3 Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran

Abstract

Objective: This study intended to evaluate if central administration of abscisic acid (ABA) alone or in combination with GW9662, a peroxisome proliferator–activated receptor γ (PPAR-γ) antagonist, could modulate learning and memory as well as hippocampal synaptic plasticity in a rat model of streptozotocin (STZ)–induced diabetes.
Materials and Methods: Intraperitoneal injection of STZ (65 mg/kg) was used to induce diabetes. Diabetic rats were than treated with intracerebroventricular (i.c.v.) administration of ABA (10, 15 and 20 µg/rat), GW9662 (3 µg/rat) or GW9662 (3 µg/rat) plus ABA (20 µg/rat).Animals’ spatial and passive avoidance learning and memory performances were assessed by Morris water maze (MWM) and shuttle box tasks, respectively. Further, in vivo electrophysiological field recordings were assessed in the CA1 region.
Results: STZ diabetic rats showed diminished learning and memory in both MWM and shuttle box tasks.  The STZ-induced memory deficits were attenuated by central infusion of ABA (10 and 20 µg/rat). Besides, STZ injection impaired long-term potentiation induction in CA1 neurons that was attenuated by ABA at 20 μg/rat. Central administration of GW9662 (3 µg/rat) alone did not modify STZ-induced spatial and passive avoidance learning and memory performances of rats. Further, GW9662 prevented ABA capacity to restore learning and memory in behavioral and electrophysiology trials.
Conclusion: Altogether, ABA ameliorates cognitive deficits in rats via activation of PPAR-γ receptor in diabetic rats.

Keywords


Ahmed A, Zeng G, Jiang D, Lin H, Azhar M,
Farooq AD, Choudhary MI, Liu X, Wang Q.
2019. Time-dependent impairments in
learning and memory in Streptozotocininduced hyperglycemic rats. Met Brain Dis,
1-16.
Arora S, Ojha SK, Vohora D. 2009.
Characterisation of streptozotocin induced
diabetes mellitus in swiss albino mice.
Global J Pharmacol, 3: 81-84.
Bahrami F, Asgari A, Hosseinmardi N,
Janahmadi M. 2019. Peroxisome
Proliferator-activated Receptor (PPAR)-γ
Modifies Aβ Neurotoxin-induced
Electrophysiological Alterations in Rat
Primary Cultured Hippocampal Neurons. Ira
J Pharm Res, 18: 1403-1418.
Bassaganya-Riera J, Guri AJ, Lu P, Climent M,
Carbo A, Sobral BW, Horne WT, Lewis SN,
Bevan DR, Hontecillas R. 2011. Abscisic
acid regulates inflammation via ligandbinding domain-independent activation of
peroxisome proliferator-activated receptor
γ. J Biol Chem, 286: 2504-2516.
Bassani TB, Bonato JM, Machado MM,
Cóppola-Segovia V, Moura EL, Zanata SM,
Oliveira RM, Vital MA. 2018. Decrease in
adult neurogenesis and neuroinflammation
are involved in spatial memory impairment
in the streptozotocin-induced model of
sporadic Alzheimer’s disease in rats. Mol
Neurobiol, 55: 4280-4296.
Bruzzone S, Bodrato N, Usai C, Guida L,
Moreschi I, Nano R, Antonioli B, Fruscione
F, Magnone M, Scarfì, S. 2008. Abscisic
acid is an endogenous stimulator of insulin
release from human pancreatic islets with
cyclic ADP ribose as second messenger. J
Biol Chem, 283: 32188-32197.
Chen H, Liu Q, Salter AM, Lomax MA. 2013.
Synergism between cAMP and PPAR
Signalling in the Initiation of UCP1 Gene
Expression in HIB1B Brown Adipocytes.
PPAR Res, 2013.
Cheng H, Shang Y, Jiang L, Shi Tl, Wang L.
2016. The peroxisome proliferators
activated receptor-gamma agonists as
therapeutics for the treatment of Alzheimer's
disease and mild-to-moderate Alzheimer's
disease: a meta-analysis. Int J Neurosci,
126: 299-307.
Costello D A, O'Leary DM, Herron CE. 2005.
Agonists of peroxisome proliferatoractivated receptor-γ attenuate the Aβmediated impairment of LTP in the
hippocampus in vitro. Neuropharmacol, 49:
359-366.
Furman B L. 2015. Streptozotocin‐induced
diabetic models in mice and rats. Curr
Protoc Pharmacol, 70: 5.47. 41-45.47. 20.
Gerozissis K. 2008. Brain insulin, energy and
glucose homeostasis; genes, environment
and metabolic pathologies. Eur J Pharmacol,
585: 38-49.
Guri AJ, Evans NP, Hontecillas R, BassaganyaRiera J. 2011. T cell PPARγ is required for
the anti-inflammatory efficacy of abscisic
acid against experimental IBD. J Nutr
Biochem, 22: 812-819.
Guri AJ, Hontecillas R, Bassaganya-Riera J.
2010. Abscisic acid synergizes with
rosiglitazone to improve glucose tolerance
Kooshki et al.
AJP, Vol. 11, No. 3, May-Jun 2021 256
and down-modulate macrophage
accumulation in adipose tissue: possible
action of the cAMP/PKA/PPAR γ axis. Clin
Nutr, 29: 646-653.
Han H, Wu Lm, Han MX, Yang WX, Wang
YX, Fang ZH. 2016. Diabetes impairs
spatial learning and memory and
hippocampal neurogenesis via BDNF in rats
with transient global ischemia. Brain Res
Bull, 124: 269-277.
Hauser F, Li Z, Waadt R, Schroeder JI .2017.
SnapShot: abscisic acid signaling. Cell, 171:
1708-1708. e1700.
Jiang L Y, Tang SS, Wang XY, Liu LP, Long
Y, Hu M, Liao MX, Ding QL, Hu W, Li JC.
2012. PPARγ agonist pioglitazone reverses
memory impairment and biochemical
changes in a mouse model of type 2 diabetes
mellitus. CNS neuroscience & therapeutics,
18: 659-666.
Khorasani A, Abbasnejad M, Esmaeili-Mahani
S. 2019.Phytohormone abscisic acid
ameliorates cognitive impairments in
streptozotocin-induced rat model of
Alzheimer's disease through PPARβ/δ and
PKA signaling. Int J Neurosci, 1-17.
Kline K G, Sussman MR, Jones AM. 2010.
Abscisic acid receptors. Plant Phys, 154:
479-482.
Kota B P, Huang TH-W, Roufogalis BD. 2005.
An overview on biological mechanisms of
PPARs. Pharmacol Res, 51: 85-94.
Landreth G, Jiang Q, Mandrekar S, Heneka M.
2008. PPARγ agonists as therapeutics for
the treatment of Alzheimer's disease.
Neurotherapeutics, 5: 481-489.
Lievens L, Pollier J, Goossens A, Beyaert R,
Staal J. 2017. Abscisic acid as pathogen
effector and immune regulator. Front Plant
Sci, 8: 587.
Lin CH, Nicol CJ, Cheng YC, Chen SJ, Yen
CH, Huang RN, Chiang MC.
2018.Rosiglitazone rescues human neural
stem cells from amyloid-beta induced ER
stress via PPARγ dependent signaling. Exp
Cell Res, 370: 312-321.
Liu Lp, Yan TH, Jiang LY, Hu W, Hu M, Wang
C, Zhang Q, Long Y, Wang JQ, Li YQ.
2013. Pioglitazone ameliorates memory
deficits in streptozotocin-induced diabetic
mice by reducing brain β-amyloid through
PPARγ activation. Acta Pharmacologica
Sinica, 34: 455.
Lotfy M, AdeghateJ, Kalasz H, Singh J,
AdeghateE. 2017. Chronic complications of
diabetes mellitus: a mini review. Curr
Diabetes Rev, 13: 3-10.
Masciopinto F, Di Pietro N, Corona C, Bomba
M, Pipino C, Curcio M, Di Castelnuovo A,
Ciavardelli D, Silvestri E, Canzoniero LM.
2012. Effects of long-term treatment with
pioglitazone on cognition and glucose
metabolism of PS1-KI, 3xTg-AD, and wildtype mice. Cell death Dis, 3: e448.
Mollashahi M, Abbasnejad M, EsmaeiliMahani S. 2018. Phytohormone abscisic
acid elicits antinociceptive effects in rats
through the activation of opioid and
peroxisome proliferator-activated receptors
β/δ. Eur J Pharmacol, 832: 75-80.
Naderi R, Esmaeili-Mahani S, Abbasnejad M.
2017. Phosphatidylinositol-3-kinase and
protein kinase C are involved in the procognitive and anti-anxiety effects of
phytohormone abscisic acid in rats. Biomed
Pharmacother, 96: 112-119.
Naderi R, Esmaeili-Mahani S, Abbasnejad M.
2019. Extracellular calcium influx through
L-type calcium channels, intracellular
calcium currents and extracellular signalregulated kinase signaling are involved in
the abscisic acid-induced precognitive and
anti-anxiety effects. Biomed Pharmacother,
109: 582-588.
Owen SC, Doak AK, Ganesh AN, Nedyalkova
L, McLaughlin CK, Shoichet BK, Shoichet
MS. 2014. Colloidal drug formulations can
explain “bell-shaped” concentration–
response curves. ACS Chem Biol, 9: 777-
784.
Paxinos G, Watson C. 1998. The rat brain in
stereotaxic CO—ordinatesEM-1. The 2nd
Edition. USA San Diego, Ac—ademic Pres,
36-34O.
Popoviç M, Biessels G-J, Isaacson RL, Gispen
WH. 2001. Learning and memory in
streptozotocin-induced diabetic rats in a
novel spatial/object discrimination task.
Behav Brain Res, 122: 201-207.
Qi CC, Ge JF, Zhou JN. 2015. Preliminary
evidence that abscisic acid improves spatial
memory in rats. Phys Behav 139: 231-239.
Raghavendra AS, Gonugunta VK, Christmann
A, Grill E. 2010. ABA perception and
signalling. Trends Plant Sci, 15: 395-401
Shonesy B C, Thiruchelvam K, Parameshwaran
K, Rahman EA, Karuppagounder SS,
Huggins KW, Pinkert CA, Amin R,
Dhanasekaran M, Suppiramaniam V. 2012.
Central insulin resistance and synaptic
ABA effects on diabetes-induced memory deficiency
AJP, Vol. 11, No. 3, May-Jun 2021 257
dysfunction in intracerebroventricularstreptozotocin injected rodents. Neurobiol
Aging, 33: 430. e435-430. e418.
Singh S, Simpson RL, Bennett RG. 2015.
Relaxin activates peroxisome proliferatoractivated receptor γ (PPARγ) through a
pathway involving PPARγ coactivator 1α
(PGC1α). J Biol Chem, 290: 950-959.
Sripetchwandee J, Pipatpiboon N,
Pratchayasakul W, Chattipakorn N,
Chattipakorn SC .2014. DPP-4 inhibitor and
PPARγ agonist restore the loss of CA1
dendritic spines in obese insulin-resistant
rats. Arch Med Res, 45: 547-552.
Struck MB, Andrutis K A, Ramirez H E, Battles
A H. 2011. Effect of a short-term fast on
ketamine–xylazine anesthesia in rats. J Am
Assoc Lab Anim Sci, 50: 344-348.
Sturla L, Mannino E, Scarfì S, Bruzzone S,
Magnone M, Sociali G, Booz V, Guida L,
Vigliarolo T, Fresia C. 2017. Abscisic acid
enhances glucose disposal and induces
brown fat activity in adipocytes in vitro and
in vivo. Biochimica et Biophysica Acta
(BBA)-Molecular and Cell Biology of
Lipids, 1862: 131-144.
Xu ZP, Li L, Bao J, Wang ZH, Zeng J, Liu EJ,
Li XG, Huang RX, Gao D, Li MZ. 2014.
Magnesium protects cognitive functions and
synaptic plasticity in streptozotocin-induced
sporadic Alzheimer’s model. PloS one, 9(9),
e108645.
Yang H, Fan S, Song D, Wang Z, Ma S, Li S,
Li X, Xu M, Xu M, Wang X. 2013. Longterm streptozotocin-induced diabetes in rats
leads to severe damage of brain blood
vessels and neurons via enhanced oxidative
stress. Mol Med Rep, 7: 431-440.
Yasmin S, Jayaprakash V. 2017.
Thiazolidinediones and PPAR orchestra as
antidiabetic agents: From past to present.
Eur J Med Chem, 126: 879-893.
Yau SY, Lee TH Y, Li A, Xu A, So KF. 2018.
Adiponectin mediates running-restored
hippocampal neurogenesis in
streptozotocin-induced type 1 diabetes in
mice. Front Neurosci, 12.
Yazir Y, Polat S, Utkan T, Aricioglu F.
2019.Role of the nitric oxide-soluble
guanylyl cyclase pathway in cognitive
deficits in streptozotocin-induced diabetic
rats. Psych Clin Psychopharmacol, 29: 34-
44.
Zocchi E, Hontecillas R, Leber A, Einerhand A,
Carbo A, Bruzzone S, Tubau-Juni N,
Philipson N, Zoccoli-Rodriguez V, Sturla L.
2017. Abscisic acid: a novel nutraceutical
for glycemic control. Front Nutr, 4: 24.