Thymoquinone loaded solid lipid nanoparticles counteracts 3-Nitropropionic acid induced motor impairments and neuroinflammation in rat model of Huntington’s disease
Defect in gene transcription, excitotoxicity, neuroinflammation and oxidative stress are the dominant disease process that causes striatal cell loss with motor abnormalities in Huntington’s disease (HD). Homogeneous pathological reminiscent of HD was extrapolated in the present study using a potent mitochondrial toxin, 3-Nitropropionic acid (3-NP). Administration of 3-NP for 14 days in the present study portends glial cell activation, N-methyl-D-aspartate (NMDA) receptor stimulation, neuroinflammation and motor deficits. The therapeutic strategy in the present study was improvised by formulating thymoquinone, a biologically active compound into a colloidal carrier namely solid lipid nanoparticles. Treatment with 10 and 20 mg/kg b.w of thymoquinone loaded solid lipid nanoparticles (TQ-SLNs) and 80 mg/kg b.w of thymoquinone suspension (TQ-S) showed a significant (P < 0.01) improvement in ATPases function in 3-NP induced animals than TQ-S (40 mg/kg b.w) treated group. TQ-SLNs (10 and 20 mg/kg) treatment also attenuated the overexpression of glial fibrillary acidic protein (GFAP), pro-inflammatory cytokines and p-p65 NFκB nuclear translocation in 3-NP exposed animals. Further, TQ-SLNs treatment desensitizes NR2B-subtype NMDA receptor, improves tyrosine hydroxylase (TH) immune reactive neurons and ameliorated the motor abnormalities in 3-NP intoxicated animals than TQ-S treated group. Hence, the study signifies that the treatment with lower doses of nanoformulated thymoquinone than thymoquinone suspension can efficiently culminate 3-NP induced HD progression in the striatum of male wistar rats.
KeywordsSolid lipid nanoparticles 3-Nitropropionic acid Huntington’s disease Thymoquinone Neuroinflammation Motor deficits
The first author is grateful to UGC-BSR for the financial support in the form of UGC-JRF Fellowship (Co/Tara/UGC-BSR/Med-Biochem/2015/613 dated 27th October 2015).
Compliance with ethical standards
Conflicts of interest
The authors declare that no conflicts of interest exist.
- Aquib M, Najmi AK, Akthar M (2015) Antidepressant effect of thymoquinone in animal models of depression. Drug Res (Stuttg) 65:490–494Google Scholar
- Cattaneo E (2003) Dysfunction of wild type huntingtin in Huntington disease. J News Physiol Sci 18:34–37Google Scholar
- Cote SL, Ribeiro-Da-Silva A, Cuello AC (1993) Immunocytochemistry II. John Wiley and Sons, New YorkGoogle Scholar
- Fiske CK, Subbarow Y (1925) The colorimetric determination of phosphorus. J Biol Chem 66:376–406Google Scholar
- Frautschy SA, Cole GM (2009) Bioavailable curcuminoid formulations for treating Alzheimer’s disease and other age-related disorders. United states US:2009/0324703 A1Google Scholar
- Gökce EC, Kahveci R, Gökce A, Cemil B, Aksoy N, Sargon MF, Kısa Ü, Erdoğan B, Güvenç Y, Alagöz F, Kahveci O (2016) Neuroprotective effects of thymoquinone against spinal cord ischemia-reperfusion injury by attenuation of inflammation, oxidative stress, and apoptosis. J Neurosurg Spine 24:949–959CrossRefGoogle Scholar
- Ismail N, Ismail M, Abu Bakar MF, Azmi NH, Basri H, Abdullah MA (2016) Modulation of hydrogen peroxide-induced oxidative stress in human neuronal cells by thymoquinone-rich fraction and thymoquinone via transcriptomic regulation of antioxidant and apoptotic signaling genes. Oxid Med Cell Longevity Article ID 2528935:1–15CrossRefGoogle Scholar
- Khan A, Vaibhav K, Javed H, Khan MM, Tabassum R, Ahmed ME, Srivastava P, Khuwaja G, Islam F, Siddiqui MS, Shafi MM, Islam F (2012) Attenuation of Abeta-induced neurotoxicity by thymoquinone via inhibition of mitochondrial dysfunction and oxidative stress. Mol Cell Biochem 369:55–65CrossRefGoogle Scholar
- Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN (2002) Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci U S A 99:2356–2361CrossRefGoogle Scholar
- Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- Novak MJ, Tabrizi SJ (2010) Huntington's disease. BMJ 341:34–40Google Scholar
- Surekha R, Sumathi T (2016) An efficient encapsulation of thymoquinone using solid lipid nanoparticle for brain targeted drug delivery: physicochemical characterization, pharmacokinetics and bio-distribution studies. IJPCR 8:1616–1624Google Scholar
- Surekha R, Aishwarya V, Sumathi T (2014) Thymoquinone loaded solid lipid nanoparticle: formulation, characterization and in-vitro cell viability assay. Int J Pharm Bio Sci 6:449–464Google Scholar
- Teunissen CE, Steinbusch HW, Angevaren M, Appels M, de Bruijn C, Prickaerts J, de Vente J (2001) Behavioural correlates of striatal glial fibrillary acidic protein in the 3-nitropropionic acid rat model: disturbed walking pattern and spatial orientation. Neuroscience 105:153–167CrossRefGoogle Scholar