D-Pinitol improves cognitive dysfunction and neuronal damage induced by isoproterenol via modulation of NF-κB/BDNF/GFAP signaling in Swiss albino mice

Document Type : Original Article

Authors

1 Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi–110062, India

2 Drug Design and Medicinal Chemistry Lab., Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi–110062, India

3 Department of Biotechnology, Jamia Millia Islamia, New Delhi 110025, India

Abstract

Objective(s): Neurological disorders are the world’s most distressing problem. The adverse effects of current medications continue to compel scientists to seek safer, more effective, and economically affordable alternatives. In this vein, we explored the effect of D-Pinitol on isoproterenol-induced neurotoxicity in mice.
Materials and Methods: Forty-two mice were randomly distributed into 7 groups each having 6 animals. Group I; received saline. Group II; received isoproterenol (ISO) 15 mg/kg/day, s.c. for 20 days. Group III, IV; received 50 and 100 mg/kg/day/oral of D-Pinitol, respectively along with ISO for 20 days. Group V; received D-Pinitol 100 mg/kg/day/oral for 20 days. Group VI; received propranolol 20 mg/kg/day/oral and ISO for 20 days. Group VII; received propranolol 20 mg/kg/day/oral for 20 days. On the 21st day after behavioral tests, blood was collected and mice were sacrificed for various biochemical, histopathological, and immunohistochemical analyses.
Results: Chronic administration of isoproterenol caused neurotoxicity, cognitive dysfunction, and histopathological changes in the brain as evidenced by increase in GFAP, oxidative stress (via SOD, CAT, TBARS, and GSH), neuroinflammation  (NF-kB, TNF-α, IL-6, and IL-10), and decrease in AchE and BDNF. Co-administration of D-Pinitol (100 mg/kg) significantly prevented these pathological alterations. The cognitive improvement was also observed through the forced swim test, elevated plus maze test, and rotarod test.
Conclusion: Our findings on D-Pinitol thus clearly established its neuroprotective role in ISO-induced neurodegeneration in Swiss albino mice.

Keywords

Main Subjects

References

1.    Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: Harms and benefits for human health. Oxid Med Cell Longev 2017; 2017:8416763-8416775.
2.    Daoud A, Mnafgui K, Turki M, Jmal S, Ayadi F, ElFeki A, et al. Cardiopreventive effect of ethanolic extract of date palm pollen against isoproterenol induced myocardial infarction in rats through the inhibition of the angiotensin-converting enzyme. ExpToxicolPathol 2017; 69:656-665.
3.    Sharma P, Verma PK, Sood S, Pankaj NK, Agarwal S, Raina R. Neuroprotective potential of hydroethanolic hull extract of Juglansregia L. on isoprenaline induced oxidative damage in brain of Wistar rats. Toxicol Rep 2021; 8:223-229.
4.    Johnson JD, Zimomra ZR, Stewart LT. Beta-adrenergic receptor activation primes microglia cytokine production. J Neuro immunol 2013; 254:161-164.
5.    Niu Y, Wan C, Zhou B, Wang J, Wang J, Chen X, et al. Aerobic exercise relieved vascular cognitive impairment via NF-κB/miR-503/BDNF pathway. Am J Transl Res 2018; 10:753-761.
6.    Maqbool A, Lattke M, Wirth T, Baumann B. Sustained, neuron specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging. Mol Neurodegener 2013; 8: 40-57.
7.    Bosak A, Gazić Smilović I, Šinko G, Vinković V, Kovarik Z. Metaproterenol, isoproterenol, and their bisdimethylcarbamate derivatives as human cholinesterase inhibitors. J Med Chem 2012; 55:6716-6723.
8.    Sarter M, Bruno JP, Parikh V. Abnormal neurotransmitter release underlying behavioral and cognitive disorders: Toward concepts of dynamic and function-specific dysregulation. Neuropsychopharmacology 2007; 32:1452-1461.
9.    Lumpkins KM, Bochicchio GV, Keledjian K, Simard JM, McCunn M, Scalea T. Glial fibrillary acidic protein is highly correlated with brain injury. J Trauma 2008; 65:778-784.
10.    Akinrinade ID, Memudu AE, Ogundele OM, Ajetunmobi OI. Interplay of glia activation and oxidative stress formation in fluoride and aluminium exposure. Pathophysiology 2015; 22:39-48.
11.    Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT. Natural products in drug discovery: Advances and opportunities. Nat Rev Drug Discov 2021; 20:200-216.
12.    Mani S, Sekar S, Barathidasan R, Manivasagam T, Thenmozhi AJ, Sevanan M, et al. Naringenin decreases α-synuclein expression and neuroinflammation in MPTP-induced Parkinson’s disease model in mice. Neurotox Res 2018; 33:656-670.
13.    Sánchez-Hidalgo M, León-González AJ, Gálvez-Peralta M, González-Mauraza NH, Martin-Cordero C. D-Pinitol: A cyclitol with versatile biological and pharmacological activities. Phytochem Rev 2021; 20:211-224.
14.    Zheng K, Zhao Z, Lin N, Wu Y, Xu Y, Zhang W. Protective effect of pinitol against inflammatory mediators of rheumatoid arthritis via inhibition of protein tyrosine phosphatase non-receptor type 22 (PTPN22). Med Sci Monit 2017; 23:1923-1932.
15.    Lee E, Lim Y, Kwon SW, Kwon O. Pinitol consumption improves liver health status by reducing oxidative stress and fatty acid accumulation in subjects with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. J Nutr Biochem 2019; 68:33-41.
16.    Cryan JF, Page ME, Lucki I. Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test. Eur J Pharmacol 2002;436:197-205.
17.    Pellow S, Chopin P, File SE, Briley M. Validation of open: Closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985; 14:149-167.
18.    Silva MI, de Aquino Neto MR, Neto PF, Moura BA, do Amaral JF, de Sousa DP, et al. Central nervous system activity of acute administration of isopulegol in mice. Pharmacol Biochem Behav 2007; 88:141-147.
19.    Claiborne AL. Catalase activity. CRC Handbook of Methods for Oxygen Radical Research. 1986:283-284.
20.    Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 1974; 47:469-474.
21.    Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968; 25:192-205.
22.    Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95:351-358.
23.    Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biocheml Pharmacol 1961; 7:88-95.
24.    Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, et al. Hypoxia induces heart regeneration in adult mice. Nature 2017; 541:222-227.
25.    Sharma S, Khan V, Najmi AK, Alam O, Haque SE. Prophylactic treatment with icariin prevents isoproterenol-induced myocardial oxidative stress via nuclear factor-like 2 activation. Pharmacog Mag 2018; 14:5227-5236.
26.    Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L. Oxidative stress in neurodegenerative diseases: From molecular mechanisms to clinical applications. Oxid Med Cell Longev 2017;2017:2525967.
27.    Di Paolo M, Papi L, Gori F, Turillazzi E. Natural products in neurodegenerative diseases: A great promise but an ethical challenge. Int J Mol Sci 2019; 20:5170-5181.
28.    Carvalho AN, Firuzi O, Joao Gama M, van Horssen J, Saso L. Oxidative stress and anti-oxidants in neurological diseases: Is there still hope?.Curr Drug Targets 2017; 18:705-718.
29.    Mo GL, Li Y, Du RH, Dai DZ, Cong XD, Dai Y. Isoproterenol induced stressful reactions in the brain are characterized by inflammation due to activation of NADPH oxidase and ER stress: Attenuated by apocynin, rehmannia complex and triterpene acids. Neurochem Res 2014; 39:719-730.
30.    Alam M, Najmi AK, Ahmad I, Ahmad FJ, Akhtar MJ, Imam SS, et al. Formulation and evaluation of nano lipid formulation containing CNS acting drug: Molecular docking, in vitro assessment and bioactivity detail in rats. Artif Cells Nanomed Biotechnol 2018; 46:46-57.
31.    Hirshman NA, Hughes Jr FM, Jin H, Harrison WT, White SW, Doan I, et al. Cyclophosphamide-induced cystitis results in NLRP3-mediated inflammation in the hippocampus and symptoms of depression in rats. Am J Physiol Renal Physiol 2020; 318:F354-F362.
32.    Deacon RM. Measuring motor coordination in mice. J Vis Exp 2013; 75:e2609.
33.    Shiotsuki H, Yoshimi K, Shimo Y, Funayama M, Takamatsu Y, Ikeda K, et al. A rotarod test for evaluation of motor skill learning. J Neurosci Methods 2010; 189:180-185.
34.    Lalkovičová M, Danielisová V. Neuroprotection and anti-oxidants. Neural Regen Res 2016; 11:865-874.
35.    Wang Y, Wang Z, Wang Y, Li F, Jia J, Song X, et al. The gut-microglia connection: Implications for central nervous system diseases. Front Immunol 2018; 9:2325-2340.
36.    Eikelenboom P, Van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, Van Gool WA. Neuroinflammation–an early event in both the history and pathogenesis of Alzheimer’s disease. Neurodegener Dis 2010; 7:38-41.
37.    Li W, Suwanwela NC, Patumraj S. Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. Microvasc Res 2016; 106:117-127.
38.    Khan A, Iqubal A, Haque SE. Combinatorial delivery of cinnamaldehyde and quercetin ameliorates isoproterenol-induced cardiac inflammation, apoptosis and myocardial infarction via modulation of NF-kB P65 and cleaved caspase-3 signaling molecules in wistar rats. Pharm Chem J 2022; 56:197-205.
39.    Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol 2019; 94:112-120.
40.    Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308:1314-1318.
41.    Calvillo M, Diaz A, Limon DI, Mayoral MA, Chánez-Cárdenas ME, Zenteno E, et al. Amyloid-β25–35 induces a permanent phosphorylation of HSF-1, but a transitory and inflammation-independent overexpression of Hsp-70 in C6 astrocytoma cells. Neuropeptides 2013; 47:339-346.
42.    Sarter M, Bruno JP, Parikh V. Abnormal neurotransmitter release underlying behavioral and cognitive disorders: Toward concepts of dynamic and function-specific dysregulation. Neuropsycho Pharmacology 2007; 32:1452-1461.
43.    McHardy SF, Wang HY, McCowen SV, Valdez MC. Recent advances in acetylcholinesterase inhibitors and reactivators: An update on the patent literature (2012-2015). Expert Opin Ther Pat 2017; 27:455-476.
44.    Zameer S, Kaundal M, Vohora D, Ali J, Najmi AK, Akhtar M. Ameliorative effect of alendronate against intracerebro ventricular streptozotocin induced alteration in neurobehavioral, neuroinflammation and biochemical parameters with emphasis on Aβ and BACE-1. Neurotoxicology 2019; 70:122-134.
45.    Hancke JL, Srivastav S, Cáceres DD, Burgos RA. A double‐blind, randomized, placebo‐controlled study to assess the efficacy of Andrographis paniculata standardized extract (ParActin®) on pain reduction in subjects with knee osteoarthritis. Phytother Res 2019; 33:1469-1479.
46.    Lu BD, Nagappan G, Lu YB. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 2014; 220:223-250.
47.    Fletcher JL, Murray SS, Xiao J. Brain-derived neurotrophic factor in central nervous system myelination: A new mechanism to promote myelin plasticity and repair. Int J Mol Sci 2018; 19:4131-4146.
48.    Siuda J, Patalong-Ogiewa M, Żmuda W, Targosz-Gajniak M, Niewiadomska E, Matuszek I, et al. Cognitive impairment and BDNF serum levels. Neurol Neurochir Pol 2017; 51:24-32.
49.    Mnafgui K, Khdhiri E, Ghazouani L, Ncir M, Zaafouri Z, Allouche N, et al. Anti-embolic and anti-oxidative effects of a novel (E)-4-amino-N′-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide against isoproterenol and vitamin-K induced ischemic stroke. Arch Physiol Biochem 2021; 127:527-540.
50.    Saroj P, Bansal Y, Singh R, Akhtar A, Sodhi RK, Bishnoi M, et al. Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington’s disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway. Inflammopharmacology 2021; 29:499-511.
51.    Kaltschmidt B, Kaltschmidt C. NF-KappaB in long-term memory and structural plasticity in the adult mammalian brain. Front Mol Neurosci 2015; 24; 8:69-79.
52.    Zhuang X, Zhan B, Jia Y, Li C, Wu N, Zhao M, et al. IL-33 in the basolateral amygdala integrates neuroinflammation into anxiogenic circuits via modulating BDNF expression. Brain Behav Immun 2022; 102:98-109.
53.    Goel R, Bhat SA, Hanif K, Nath C, Shukla R. Angiotensin II receptor blockers attenuate lipopolysaccharide-induced memory impairment by modulation of NF-κB-mediated BDNF/CREB expression and apoptosis in spontaneously hypertensive rats. Mol Neurobiol 2018; 55:1725-1739.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 3
March 2024
Pages 326-334

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