Adenosine A1 Receptor Agonist Protects Against Hippocampal Neuronal Injury After Lithium Chloride-Pilocarpine- Induced Epilepsy

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. (REV INVEST CLIN. 2019;71:116-23)

Early Developmental PMCA2b Expression Protects From Ketamine-Induced Apoptosis and GABA Impairments in Differentiating Hippocampal Progenitor Cells

“…For instance, strong upregulation of Adora1 encoding adenosine A1 receptor has been revealed in response to PMCA2b expression in the presence of ketamine. Several recent reports have demonstrated this receptor to be neuroprotective (Gholinejad et al, 2018 ; Xiao et al, 2019 ; Zhang et al, 2020 ). In adult brain, treatment with ketamine was associated with intensified formation of the PMCA/PSD-95/NMDAR1 complex (Lisek et al, 2017 ), which is thought to tether PMCA to the site of massive Ca 2+ influx.…”

FOXO4 alleviates hippocampal neuronal damage in epileptic mice via the miR‐138‐5p/ROCK2 axis

“…Epilepsy (EP) is a central nervous disease that has led to approximately 70 million cases of EP worldwide, with a relatively higher incidence in infants and elderly populations (Thijs et al, 2019). The episodes of EP are an important contributor to neuronal damage in the hippocampal region (Xiao et al, 2019). On the other hand, FOXOs are a type of transcription factor associated with EP-induced neuronal death (Kim et al, 2014).…”

Maternal lithium chloride exposure alters the neuroendocrine‐cytokine axis in neonatal albino rats

“…In fact, the intracellular GSK-3β pathway regulates neurogenesis and cellular determination (Korur et al, 2009;Zhang et al, 2019). Thus, lithium could cause memory disorders and seizures (Bartha et al, 2002), neurotoxicity (Ahmad et al, 2011;Aral & Vecchio-Sadus, 2008) and epilepsy (Xiao et al, 2019). Alternatively, lithium can exert this disturbance by initiating cellular hypothyroidism (Bolaris, Margarity, & Valcana, 1995), reducing the birth weight (Harari et al, 2015), decreasing the energy balance (Brietzke, Stabellini, Grassi-Oliveira, & Lafer, 2011), increasing cytokine imbalances (Grignon & Bruguerolle, 1996) and activating DNA fragmentation in cerebrum of rats (Shao, Young, & Wang, 2005).…”

“…Importantly, lithium can decrease the level of plasma adiponectin (Soeiro-de-Souza et al, 2014) and stop the adipogenesis process (Longo et al, 2004;Ross et al, 2000). Furthermore, lithium can initiate brain disorders, coma, seizures, neural toxicity (Ahmad, Elnakady, Farooq, & Wadaan, 2011;Aral & Vecchio-Sadus, 2008;Bartha, Marksteiner, Bauer, & Benke, 2002) and epilepsy (Xiao et al, 2019) via disrupting the levels of Serotonin (5-HT) (Ayano, 2016;Stahl, 2018;Yadav et al, 2009), Dopamine (DA) (Malhi, 2013;McFarlane et al, 2011;O'Donnell & Gould, 2007) and Norepinephrine (NE) (De Bartolomeis, Tomasetti, Cicale, Yuan, & Manji, 2012;Sastre, Nicolay, Bruguerolle, & Portugal, 2005;Schildkraut, Logue, & Dodge, 1969). Interestingly, thyroid disorders can perturb the production of cytokines De Vito et al, 2011;Silva, Ocarino, & Serakides, 2014), causing brain disorders during growth/ development (Andersen, Andersen, Vestergaard, & Olsen, 2018;O'Shaughnessy et al, 2018O'Shaughnessy et al, , 2019Thompson et al, 2018).…”