Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling of Effect of Naringenin and Its Surface Modified Nanocarriers on Associated and Core Behaviors of Autism Spectrum Disorders (ASD)

Abstract

The pharmacokinetic and pharmacodynamic (PK-PD) model was developed to describe the relationship between plasma/brain concentration of naringenin and its nanocarriers with behavioral and biochemical alterations in a rat model of autism spectrum disorders (ASD). Behavioral parameters like sensorimotor dysfunction, hyperlocomotion, anxiety-like behavior, social interaction, and repetitive behavior were investigated by rotarod, actophotometer, open-field, reciprocal social interaction, and repetitive self-grooming test respectively. Naringenin was administered in doses (25, 50, and 100 mg/kg) and in the form of its uncoated and glutathione as well as tween 80–coated PLGA nanocarriers (25 mg/kg) thrice daily (8 hourly). Sigmoid E_max model was applied to study the relationship between the concentration of naringenin in plasma/brain and behavioral effects (in terms of sensorimotor dysfunction, locomotor activity, anxiety-like behavior, social interaction ability, repetitive behavior) as well as biochemical changes (plasma levels of TNF-α, MMP-9, and HSP-70, and Pgp at BBB). Model parameters such as E_o, E_max, and EC₅₀ indicate that maximum effect occurred after administration of GSH-coated naringenin nanoparticles and the minimum effect occurred with the 25 mg/kg dose of unencapsulated naringenin. The R² value of 0.99 and small Akaike information criterion indicate the goodness of fit of the model. The PK-PD modeling done by sigmoid E_max model showed a positive correlation between plasma/brain drug concentration and neuroinflammatory markers as well as behaviors consistent with the ASD phenotype.  

Key words

pharmacokinetic and pharmacodynamic (PK-PD) - autism spectrum disorders (ASD) - naringenin - glutathione - tween 80 - nanoparticles

• References

• 1 American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013. Accessed at http://www.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596
• 2 Estabillo JA, Matson JL, Cervantes PE. Autism symptoms and problem behaviors in children with and without developmental regression. J Dev Phys Disabil 2018; 30: 17-26
• 3 World Health Organization. Autism spectrum disorders. 2017; Accessed at, http://www.who.int/mediacentre/factsheets/autism-spectrum-disorders/en/
• 4 Holt R, Monaco AP. Links between genetics and pathophysiology in the autism spectrum disorders. EMBO Mol Med 2011; 3: 438-450
• 5 Santangelo SL, Tsatsanis K. What is known about autism: genes, brain, and behavior. Am J Pharmacogenomics 2005; 5: 71-92
• 6 Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J, Reaven J, Reynolds AM, Rice CE, Schendel D, Windham GC. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007; 28: 235-258
• 7 EJH Jones, Gliga T, Bedford R, Charman T, Johnson MH. Developmental pathways to autism: a review of prospective studies of infants at risk. Neurosci Biobehav Rev 2014; 39: 1-33
• 8 LaSalle JM. Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J Hum Genet 2013; 58: 396-401
• 9 Modabbernia A, Velthorst E, Reichenberg A. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Mol Autism 2017; 8: 13
• 10 Ciernia AV, Laufer BI, Dunaway KW, Mordaunt CE, Coulson RL, Yasui DH, LaSalle JM. Epigenomic convergence of genetic and immune risk factors in autism brain. bioRxiv 270827; doi: https://doi.org/10.1101/ 270827; Accessed at: https://www.biorxiv.org/content/10.1101/ 270827v2
• 11 Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism spectrum disorders: Immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry 2012; 17: 389-401
• 12 Nadeem A, Ahmad SF, Attia SM, Bakheet SA, Al-Harbi NO, AL-Ayadhi LY. Activation of IL-17 receptor leads to increased oxidative inflammation in peripheral monocytes of autistic children. Brain Behav Immun 2018; 67: 335-344
• 13 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57: 67-81
• 14 Bjorkland G, Saad K, Chirumbolo S, Kern JK, Geier DA, Geier MR, Urbina MA. Immune dysfunction and neuroinflammation in autism spectrum disorder. Acta Neurobiol Exp 2016; 76: 257-268
• 15 Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology 2002; 46: 76-84
• 16 Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999; 135: 559-563
• 17 MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F, Taylor AR, Kavaliers M, Ossenkopp KP. Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 2007; 176: 149-169
• 18 Choi J, Lee S, Won J, Jin Y, Hong Y, Hur TY, Kim JH, Lee SR, Hong Y. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One 2018; 13: e0192925
• 19 Bhandari R, Kuhad A. Neuropsychopharmacotherapeutic efficacy of curcumin in experimental paradigm of autism spectrum disorders. Life Sci 2015; 141: 156-169
• 20 Bhandari R, Kuhad A. Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int 2017; 103: 8-23
• 21 Bhandari R, Paliwal JK, Kuhad A. Naringenin and its nanocarriers as potential phytotherapy for autism spectrum disorders. J Funct Foods 2018; 47: 361-375
• 22 Felgines C, Texier O, Morand C, Manach C, Scalbert A, Régerat F, Rémésy C. Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol 2000; 279: G1148-G1154
• 23 Kumar S, Tiku AB. Biochemical and molecular mechanisms of radioprotective effects of naringenin, a phytochemical from citrus fruits. J Agric Food Chem 2016; 64: 1676-1685
• 24 Nahmias Y, Goldwasser J, Casali M, Van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology 2008; 47: 1437-1445
• 25 Yi LT, Liu B Bin, Li J, Luo L, Liu Q, Geng D, Tang Y, Xia Y, Wu D. BDNF signaling is necessary for the antidepressant-like effect of naringenin. Prog Neuro-Psychopharmacology. Biol Psychiatry 2014; 48: 135-141
• 26 Wu LH, Lin C, Lin HY, Liu YS, Wu CYJ, Tsai CF, Chang PC, Yeh WL, Lu DY. Naringenin suppresses neuroinflammatory responses through inducing suppressor of cytokine signaling 3 expression. Mol Neurobiol 2016; 53: 1080-1091
• 27 Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther 2001; 90: 157-177
• 28 Ratnam DV, Ankola DD, Bhardwaj V, Sahana DK. Kumar MNVR. Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. J Control Release 2006; 113: 189-207
• 29 Yen FL, Wu TH, Lin LT, Cham TM, Lin CC. Naringenin-loaded nanoparticles improve the physicochemical properties and the hepatoprotective effects of naringenin in orally-administered rats with CCl(4)-induced acute liver failure. Pharm Res 2009; 26: 893-902
• 30 Chien JY, Friedrich S, Heathman MA, de Alwis DP, Sinha V. Pharmacokinetics/pharmacodynamics and the stages of drug development: role of modeling and simulation. AAPS J 2005; 7: E544-E559
• 31 Danhof M, de Lange ECM, Della Pasqua OE, Ploeger BA, Voskuyl RA. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research. Trends Pharmacol Sci 2008; 29: 186-191
• 32 Meibohm B, Derendorf H. Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling. Int J Clin Pharmacol Ther 1997; 35: 401-413
• 33 Wright DFB, Winter HR, Duffull SB. Understanding the time course of pharmacological effect: a PKPD approach. Br J Clin Pharmacol 2011; 71: 815-823
• 34 Khan DD, Friberg LE, Nielsen EI. A pharmacokinetic-pharmacodynamic (PKPD) model based on in vitro time-kill data predicts the in vivo PK/PD index of colistin. J Antimicrob Chemother 2016; 71: 1881-1884
• 35 Shargel L, Wu-Pong S, Yu ABC. Applied Biopharmaceutics & Pharmacokinetics. 5^th ed New York: McGraw-Hill Medical; 2005: 527-563
• 36 MacFabe DF, Rodríguez-Capote K, Hoffman JE, Franklin AE, Mohammad-Asef Y, Taylor AR, Boon F, Cain DP, Kavaliers M, Possmayer F, Ossenkopp KP. A novel rodent model of autism: intraventricular infusions of propionic acid increase locomotor activity and induce neuroinflammation and oxidative stress in discrete regions of adult rat brain. Am J Biochem Biotechnol 2008; 4: 146-166
• 37 El-Ansary AK, Bacha A Ben, Kotb M. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. J Neuroinflammation 2012; 9: 661
• 38 Shultz SR, Macfabe DF, Martin S, Jackson J, Taylor R, Boon F, Ossenkopp KP, Cain DP. Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long-Evans rat: Further development of a rodent model of autism. Behav Brain Res 2009; 200: 33-41
• 39 Abdallah MW, Michel TM. Matrix metalloproteinases in autism spectrum disorders. J Mol Psychiatry 2013; 1: 16
• 40 González-Fraguela ME, Hung MD, Vera H, Maragoto C, Noris E, Blanco L, Galvizu R, Robinson M. Oxidative stress markers in children with autism spectrum disorders. British J Med Res 2013; 3: 307-317
• 41 Wu LH, Lin C, Lin HY, Liu YS, Wu CYJ, Tsai CF, Chang PC, Yeh WL, Lu DY. Naringenin suppresses neuroinflammatory responses through inducing suppressor of cytokine signaling 3 expression. Mol Neurobiol 2016; 53: 1080-1091
• 42 Wilson B, Samanta MK, Santhi K, Kumar KPS, Paramakrishnan N, Suresh B. Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles. Eur J Pharm Biopharm 2008; 70: 75-84
• 43 Jain A, Jain A, Garg NK, Tyagi RK, Singh B, Katare OP, Webster TJ, Soni V. Surface engineered polymeric nanocarriers mediate the delivery of transferrin-methotrexate conjugates for an improved understanding of brain cancer. Acta Biomater 2015; 24: 140-151
• 44 Grover A, Hirani A, Pathak Y, Sutariya V. Brain-targeted delivery of docetaxel by glutathione-coated nanoparticles for brain cancer. AAPS PharmSciTech 2014; 15: 1562-1568
• 45 Geldenhuys W, Mbimba T, Bui T, Harrison K, Sutariya V. Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers. J Drug Target 2011; 19: 837-845
• 46 Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule Formation by interfacial polymer deposition following solvent displacement. Int J Pharm 1989; 55: R1-R4
• 47 Dunham NW, Myua TS. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc Am Pharm Assoc (Baltim) 1957; 46: 208-209
• 48 Sachdeva AK, Kuhad A, Chopra K. Epigallocatechin gallate ameliorates behavioral and biochemical deficits in rat model of load-induced chronic fatigue syndrome. Brain Res Bull 2011; 86: 165-172
• 49 Raghavendra V, Chopra K, Kulkarni SK. Brain renin angiotensin system (RAS) in stress-induced analgesia and impaired retention. Peptides 1999; 20: 335-342
• 50 Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 2010; 11: 490-502
• 51 Moretti P, Bouwknecht JA, Teague R, Paylor R, Zoghbi HY. Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 2005; 14: 205-220
• 52 Bhandari R, Kuhad A, Paliwal JK, Kuhad A. Development of a new, sensitive, and robust analytical and bio-analytical RP- HPLC method for in vitro and in vivo quantification of naringenin in polymeric nanocarriers. J Anal Sci Technol 2019; 10: 11