Alzheimer's Disease (AD) is one of the commonest neural degenerations in an aging population, and has become a global health challenge. 2-(2-benzofuranyl)-2-imidazoline (2-BFI) was reported to effectively improve the neural damage of patients with neuropathological disorders. In the present study, we investigated the effect of 2-BFI on the improvement of antioxidative, inflammation, and apoptosis in AD rats. Sprague-Dawley rats (2 months old, ) were used in this study and after injection of into hippocampal CA1 (Cornu Ammonis) region, the rats were given high, moderate and low dose of 2-BFI though intraperitoneal (i.p.) injection. Then spatial memory and navigation ability were analyzed by Morris water maze. For molecular testing, chemical colorimetry, ELISA and immunoblotting were performed to measure the activities of antioxidative enzymes, the abundance of immune cytokines and expression of apoptotic proteins, respectively. Hematoxylin and Eosin staining were used to analyze the pathological changes. We observed that 2-BFI significantly ameliorated the learning and memory abilities in rat models with AD by dosage treatment, as demonstrated by the shortened learning latency and greater times of travel across the platform quadrant. Additionally, reactive oxygen species (ROS) and malondialdehyde (MDA), were decreased after treatment on 2-BFI with dosage dependency, while the activities of superoxidase dismutase (SOD) and (GPX) glutathione peroxidase were in turn enhanced, suggesting that 2-BFI could protect the antioxidative enzymes and reduce oxidative stress in the hippocampus. Moreover, the expression of inflammatory factors including TNF-a and IL- were decreased after 2-BFI treatment. Additionally, neuronal apoptosis was also attenuated, as shown by Western blot results. Taken together, the cognitive impairment in AD rats could be significantly improved by 2-BFI in a dose-dependent manner through suppressing oxidant accumulation, inhibition of inflammatory response, thus enhancing neural viability.
AlzheimerA., StelzmannR.A., SchnitzleinH.N. and MurtaghF.R., An English translation of Alzheimer's 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”, Clin Anat8 (1995), 429–431. doi:10.1002/ca.980080612.
2.
BanoD. and NicoteraP., signals and neuronal death in brain ischemia, Stroke38 (2007), 674–676. doi:10.1161/01.STR.0000256294.46009.29.
3.
BealM.F., Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment, Neurobiol Aging26 (2005), 585–586. doi:10.1016/j.neurobiolaging.2004.09.022.
4.
BoronatM.A., OlmosG. and Garcia-SevillaJ.A., Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands, Br J Pharmacol125 (1998), 175–185. doi:10.1038/sj.bjp.0702031.
5.
CetinF. and DincerS., The effect of intrahippocampal beta amyloid (1-42) peptide injection on oxidant and antioxidant status in rat brain, Ann N Y Acad Sci1100 (2007), 510–517. doi:10.1196/annals.1395.056.
6.
ChengX., ShenY. and LiR., Targeting TNF: A therapeutic strategy for Alzheimer's disease, Drug Discov Today19 (2014), 1822–1827. doi:10.1016/j.drudis.2014.06.029.
7.
ChristenY., Oxidative stress and Alzheimer disease, Am J Clin Nutr71 (2000), 621S–629S.
8.
ChristensenM.A., ZhouW., QingH., LehmanA., PhilipsenS. and SongW., Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1, Mol Cell Biol24 (2004), 865–874. doi:10.1128/MCB.24.2.865-874.2004.
9.
Del RioD., StewartA.J. and PellegriniN., A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress, Nutr Metab Cardiovasc Dis15 (2005), 316–328. doi:10.1016/j.numecd.2005.05.003.
10.
EngL.F. and GhirnikarR.S., GFAP and astrogliosis, Brain Pathol4 (1994), 229–237. doi:10.1111/j.1750-3639.1994.tb00838.x.
11.
EngL.F., YuA.C. and LeeY.L., Astrocytic response to injury, Prog Brain Res94 (1992), 353–365. doi:10.1016/S0079-6123(08)61764-1.
12.
EvansP.H., Free radicals in brain metabolism and pathology, Br Med Bull49 (1993), 577–587. doi:10.1093/oxfordjournals.bmb.a072632.
13.
FerrariF., FiorentinoS., MennuniL., GarofaloP., LetariO., MandelliS., GiordaniA., LanzaM. and CaselliG., Analgesic efficacy of CR4056, a novel imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain, J Pain Res4 (2011), 111–125. doi:10.2147/JPR.S18353.
14.
FialaM., Re-balancing of inflammation and abeta immunity as a therapeutic for Alzheimer's disease-view from the bedside, CNS Neurol Disord Drug Targets9 (2010), 192–196. doi:10.2174/187152710791012044.
15.
GackowskiD., RozalskiR., SiomekA., DziamanT., NicponK., KlimarczykM., AraszkiewiczA. and OlinskiR., Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia, J Neurol Sci266 (2008), 57–62. doi:10.1016/j.jns.2007.08.041.
16.
Garcia-SevillaJ.A., EscribaP.V. and GuimonJ., Imidazoline receptors and human brain disorders, Ann N Y Acad Sci881 (1999), 392–409. doi:10.1111/j.1749-6632.1999.tb09388.x.
17.
GhasemiR., ZarifkarA., RastegarK., MaghsoudiN. and MoosaviM., Repeated intra-hippocampal injection of beta-amyloid 25-35 induces a reproducible impairment of learning and memory: Considering caspase-3 and MAPKs activity, Eur J Pharmacol726 (2014), 33–40. doi:10.1016/j.ejphar.2013.11.034.
18.
GreilbergerJ., KoidlC., GreilbergerM., LamprechtM., SchroecksnadelK., LeblhuberF., FuchsD. and OettlK., Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer's disease, Free Radic Res42 (2008), 633–638. doi:10.1080/10715760802255764.
19.
GriffinW.S., ShengJ.G., GentlemanS.M., GrahamD.I., MrakR.E. and RobertsG.W., Microglial interleukin-1 alpha expression in human head injury: Correlations with neuronal and neuritic beta-amyloid precursor protein expression, Neurosci Lett176 (1994), 133–136. doi:10.1016/0304-3940(94)90066-3.
20.
GriffinW.S., ShengJ.G., RobertsG.W. and MrakR.E., Interleukin-1 expression in different plaque types in Alzheimer's disease: Significance in plaque evolution, J Neuropathol Exp Neurol54 (1995), 276–281. doi:10.1097/00005072-199503000-00014.
21.
HanZ., ZhangH.X., TianJ.S., ZhengR.Y. and HouS.T., 2-(-2-benzofuranyl)-2-imidazoline induces Bcl-2 expression and provides neuroprotection against transient cerebral ischemia in rats, Brain Res1361 (2010), 86–92. doi:10.1016/j.brainres.2010.09.029.
22.
HardyJ. and SelkoeD.J., The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics, Science297 (2002), 353–356. doi:10.1126/science.1072994.
23.
HauserS.L., DoolittleT.H., LincolnR., BrownR.H. and DinarelloC.A., Cytokine accumulations in CSF of multiple sclerosis patients: Frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6, Neurology40 (1990), 1735–1739. doi:10.1212/WNL.40.11.1735.
24.
HeP., ZhongZ., LindholmK., BerningL., LeeW., LemereC., StaufenbielM., LiR. and ShenY., Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice, J Cell Biol178 (2007), 829–841. doi:10.1083/jcb.200705042.
25.
HetierE., AyalaJ., DenefleP., BousseauA., RougetP., MallatM. and ProchiantzA., Brain macrophages synthesize interleukin-1 and interleukin-1 mRNAs in vitro, J Neurosci Res21 (1988), 391–397. doi:10.1002/jnr.490210230.
26.
JiangS.X., ZhengR.Y., ZengJ.Q., LiX.L., HanZ. and HouS.T., Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists, Eur J Pharmacol629 (2010), 12–19. doi:10.1016/j.ejphar.2009.11.063.
27.
KolarovaM., Garcia-SierraF., BartosA., RicnyJ. and RipovaD., Structure and pathology of tau protein in Alzheimer disease, Int J Alzheimers Dis2012 (2012), 731526.
28.
LiJ.X., ZhangY. and WinterJ.C., Morphine-induced antinociception in the rat: Supra-additive interactions with imidazoline I(2) receptor ligands, Eur J Pharmacol669 (2011), 59–65. doi:10.1016/j.ejphar.2011.07.041.
29.
LiR., YangL., LindholmK., KonishiY., YueX., HampelH., ZhangD. and ShenY., Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death, J Neurosci24 (2004), 1760–1771. doi:10.1523/JNEUROSCI.4580-03.2004.
30.
MattsonM.P., Pathways towards and away from Alzheimer's disease, Nature430 (2004), 631–639. doi:10.1038/nature02621.
31.
McKhannG.M., KnopmanD.S., ChertkowH., HymanB.T., JackC.R.Jr., KawasC.H., KlunkW.E., KoroshetzW.J., ManlyJ.J., MayeuxR.et al., The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease, Alzheimers Dement7 (2011), 263–269. doi:10.1016/j.jalz.2011.03.005.
32.
MecocciP., CherubiniA., BealM.F., CecchettiR., ChionneF., PolidoriM.C., RomanoG. and SeninU., Altered mitochondrial membrane fluidity in AD brain, Neurosci Lett207 (1996), 129–132. doi:10.1016/0304-3940(96)12509-X.
33.
MoussaC., HebronM., HuangX., AhnJ., RissmanR.A., AisenP.S. and TurnerR.S., Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease, J Neuroinflammation14 (2017), 1. doi:10.1186/s12974-016-0779-0.
34.
PadurariuM., CiobicaA., DobrinI. and StefanescuC., Evaluation of antioxidant enzymes activities and lipid peroxidation in schizophrenic patients treated with typical and atypical antipsychotics, Neurosci Lett479 (2010), 317–320. doi:10.1016/j.neulet.2010.05.088.
35.
PiletzJ.E., HalarisA. and ErnsbergerP.R., Psychopharmacology of imidazoline and alpha 2-adrenergic receptors: Implications for depression, Crit Rev Neurobiol9 (1994), 29–66.
36.
ReddyP.H. and BealM.F., Are mitochondria critical in the pathogenesis of Alzheimer's disease?, Brain Res Brain Res Rev49 (2005), 618–632. doi:10.1016/j.brainresrev.2005.03.004.
SalminenA., OjalaJ., KauppinenA., KaarnirantaK. and SuuronenT., Inflammation in Alzheimer's disease: Amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors, Prog Neurobiol87 (2009), 181–194. doi:10.1016/j.pneurobio.2009.01.001.
39.
SampsonC., ZhangY., Del BelloF. and LiJ.X., Effects of imidazoline I2 receptor ligands on acute nociception in rats, Neuroreport23 (2012), 73–77. doi:10.1097/WNR.0b013e32834e7db3.
40.
ShenY., HeP., ZhongZ., McAllisterC. and LindholmK., Distinct destructive signal pathways of neuronal death in Alzheimer's disease, Trends Mol Med12 (2006), 574–579. doi:10.1016/j.molmed.2006.10.002.
41.
ShengJ.G., ItoK., SkinnerR.D., MrakR.E., RovnaghiC.R., Van EldikL.J. and GriffinW.S., In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis, Neurobiol Aging17 (1996), 761–766. doi:10.1016/0197-4580(96)00104-2.
42.
ShengJ.G., MrakR.E. and GriffinW.S., Microglial interleukin-1 alpha expression in brain regions in Alzheimer's disease: Correlation with neuritic plaque distribution, Neuropathol Appl Neurobiol21 (1995), 290–301. doi:10.1111/j.1365-2990.1995.tb01063.x.
43.
SinghC., AhmadI. and KumarA., Pesticides and metals induced Parkinson's disease: Involvement of free radicals and oxidative stress, Cell Mol Biol (Noisy-le-grand)53 (2007), 19–28.
44.
SmithM.A., Oxidative stress and iron imbalance in Alzheimer disease: How rust became the fuss!, J Alzheimers Dis9 (2006), 305–308. doi:10.3233/JAD-2006-9S334.
45.
SmithM.A., NunomuraA., ZhuX., TakedaA. and PerryG., Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease, Antioxid Redox Signal2 (2000), 413–420. doi:10.1089/15230860050192198.
46.
ThornD.A., ZhangY., PengB.W., WinterJ.C. and LiJ.X., Effects of imidazoline I(2) receptor ligands on morphine- and tramadol-induced antinociception in rats, Eur J Pharmacol670 (2011), 435–440. doi:10.1016/j.ejphar.2011.09.173.
47.
TouzaniO., BoutinH., ChuquetJ. and RothwellN., Potential mechanisms of interleukin-1 involvement in cerebral ischaemia, J Neuroimmunol100 (1999), 203–215. doi:10.1016/S0165-5728(99)00202-7.
48.
TownT., Inflammation, immunity, and Alzheimer's disease, CNS Neurol Disord Drug Targets9 (2010), 129–131. doi:10.2174/187152710791012008.
49.
TsukudaK., MogiM., IwanamiJ., MinL.J., SakataA., JingF., IwaiM. and HoriuchiM., Cognitive deficit in amyloid-beta-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-gamma activation, Hypertension54 (2009), 782–787. doi:10.1161/HYPERTENSIONAHA.109.136879.
50.
WangP., WangZ.W., LinF.H., HanZ., HouS.T. and ZhengR.Y., 2-BFI attenuates experimental autoimmune encephalomyelitis-induced spinal cord injury with enhanced B-CK, CaATPase, but reduced calpain activity, Biochem Biophys Res Commun406 (2011), 152–157. doi:10.1016/j.bbrc.2011.02.018.
51.
WangX., WangW., LiL., PerryG., LeeH.G. and ZhuX., Oxidative stress and mitochondrial dysfunction in Alzheimer's disease, Biochim Biophys Acta1842 (2014), 1240–1247. doi:10.1016/j.bbadis.2013.10.015.
52.
Wyss-CorayT., Inflammation in Alzheimer disease: Driving force, bystander or beneficial response?, Nat Med12 (2006), 1005–1015.
