2019, Number 2
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Rev Invest Clin 2019; 71 (2)
Adenosine A1 Receptor Agonist Protects Against Hippocampal Neuronal Injury After Lithium Chloride-Pilocarpine- Induced Epilepsy
Xiao Q, Tang H, Kong L, Ji H, Liu Y, Cui G
Language: English
References: 23
Page: 116-123
PDF size: 550.45 Kb.
ABSTRACT
Background: Adenosine A1 receptor (AA1R) is widely present in the central nervous system, exerting brain protective antiepileptic
effects, mainly by binding corresponding G proteins. We evaluated the neuroprotective effects of AA1R on hippocampal
neuronal injury after lithium chloride-pilocarpine-induced epilepsy in rats.
Materials and Methods: A total of 60 male
SD rats were randomly divided into four groups (n = 15/group): normal control, epilepsy, epilepsy + AA1R antagonist (DPCPX),
and epilepsy + AA1R agonist (2-CAdo). An epilepsy model was established through kindling by lithium chloride-pilocarpine.
The four groups were observed on days 1, 14, and 30. Pathological and morphological changes of hippocampal neurons were
observed by HE staining; apoptosis was detected by TUNEL assay. Caspase-3 and GABA receptor expressions were detected
by Western blot.
Results: In the hippocampal CA3 area of the epilepsy group, the cellular structure was not neatly arranged,
and some neurons were swelling, thick, and incomplete. Compared with the epilepsy group at the same time point, cells in the
epilepsy + DPCPX group had an increased distortion, disorganization, edema, cytoplasmic vacuoles, and degeneration. In the
epilepsy + 2-CAdo group, cell arrangement was regular and orderly, and structural damages were lessened. Compared with
the normal control group at the same time point, the epilepsy group underwent evident neuronal apoptosis, with a significantly
higher apoptotic index (AI) (
p ‹ 0.05). Compared with the epilepsy group, the neuronal apoptosis of the epilepsy +
DPCPX group was boosted, and the AI significantly increased (
p ‹ 0.05). The neuronal apoptosis of the epilepsy + 2-CAdo
group was inhibited, and the AI significantly decreased (
p ‹ 0.05). Compared with the epilepsy group, the caspase-3 expression
levels of the epilepsy + DPCPX group on days 14 and 30 were significantly upregulated (
p ‹ 0.05), but those of the
epilepsy + 2-CAdo group were significantly downregulated (
p ‹ 0.05).
Conclusions: AA1R abated cell edema and reduced
apoptosis, exerting neuroprotective effects on hippocampal neuronal injury after lithium chloride-pilocarpine-induced epilepsy.
REFERENCES
Heck CN, King-Stephens D, Massey AD, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS system pivotal trial. Epilepsia. 2014;55: 432-41.
Nascimento FP, Macedo-Júnior SJ, Pamplona FA, et al. Adenosine A1 receptor-dependent antinociception induced by inosine in mice: pharmacological, genetic and biochemical aspects. Mol Neurobiol. 2015;51:1368-78.
Dennissen FJ, Anglada-Huguet M, Sydow A, Mandelkow E, Mandelkow EM. Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human tau ΔK280. Proc Natl Acad Sci U S A. 2016;113:11597-602.
Rivera-Oliver M, Díaz-Ríos M. Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review. Life Sci. 2014; 101:1-9.
Hohoff C, Garibotto V, Elmenhorst D, et al. Association of adenosine receptor gene polymorphisms and in vivo adenosine A1 receptor binding in the human brain. Neuropsychopharmacology. 2014;39:2989-99.
Serpa A, Correia S, Ribeiro JA, Sebastião AM, Cascalheira JF. The combined inhibitory effect of the adenosine A1 and cannabinoid CB1 receptors on cAMP accumulation in the hippocampus is additive and independent of A1 receptor desensitization. BioMed Res Int. 2015;2015:872684.
Thomas TP, Shih TM. The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology. United States: US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground United States; 2016.
Stockwell J, Jakova E, Cayabyab FS. Adenosine A1 and A2A receptors in the brain: current research and their role in neurodegeneration. Molecules. 2017;22:E676.
Cheng P, Ren Y, Bai S, et al. Chronic cerebral ischemia induces downregulation of A1 adenosine receptors during white matter damage in adult mice. Cell Mol Neurobiol. 2015;35:1149-56.
Hu J, Quick MW. Substrate-mediated regulation of gammaaminobutyric acid transporter 1 in rat brain. Neuropharmacology. 2008;54:309-18.
Stubbs B, Vancampfort D, Rosenbaum S, et al. An examination of the anxiolytic effects of exercise for people with anxiety and stress-related disorders: a meta-analysis. Psychiatry Res. 2017; 249:102-8.
Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972;32:281-94.
Zhong M, Song WL, Xu YC, Ye Y, Feng LY. Paeoniflorin ameliorates ischemic neuronal damage in vitro via adenosine A1 receptor- mediated transactivation of epidermal growth factor receptor. Acta Pharmacol Sin. 2015;36:298-310.
EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360-70.
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55:475-82.
Yin D, Liu YY, Wang TX, et al. Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model. Psychopharmacology (Berl). 2016;233: 281-93.
Liu XH, Xiang SJ, Qi Y. Histopathological changes of hippocampus after acute epilepsy induced by pentylenetetrazole in rats. Chin Pharmacol Bull. 2015;31:514-8.
André V, Dubé C, François J, et al. Pathogenesis and pharmacology of epilepsy in the lithium-pilocarpine model. Epilepsia. 2007; 48 Suppl 5:41-7.
Hanaya R, Sasa M, Sugata S, et al. Hippocampal cell loss and propagation of abnormal discharges accompanied with the expression of tonic convulsion in the spontaneously epileptic rat. Brain Res. 2010;1328:171-80.
Patel HC, Ross FM, Heenan LE, et al. Neurodegenerative actions of interleukin-1 in the rat brain are mediated through increases in seizure activity. J Neurosci Res. 2006;83:385-91.
Tan Z, Sankar R, Shin D, et al. Differential induction of p53 in immature and adult rat brain following lithium-pilocarpine status epilepticus. Brain Res. 2002;928:187-93.
Faherty CJ, Xanthoudakis S, Smeyne RJ. Caspase-3-dependent neuronal death in the hippocampus following kainic acid treatment. Brain Res Mol Brain Res. 1999;70:159-63.
Reid CA, Kim T, Phillips AM, et al. Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology. 2013;80:1003-8.