CREB Protects against Temporal Lobe Epilepsy Associated with Cognitive Impairment by Controlling Oxidative Neuronal Damage

Abstract

Background: Cognitive dysfunction as a common comorbidity of epilepsy often manifests as learning and memory impairments in patients with temporal lobe epilepsy (TLE). The pathogenetic molecular mechanisms underlying epilepsy-associated cognitive dysfunction are incompletely understood. We investigated the role of cAMP response element binding protein (CREB) and its downstream signaling pathways in the pathogenesis of cognitive impairment in mice with TLE. Methods: Plasmid vectors of CREB-specific short-hairpin RNAs and CREB cDNA were prepared and transfected into primary neurons. Neuronal apoptosis and mitochondrial oxidative stress were assessed by flow cytometry. For in vivo studies, TLE in mice was induced by pilocarpine injection, and TLE-associated memory decline was evaluated using the Morris water maze after treatment with the CREB inhibitor 666-15, with or without the mitochondriaspecific antioxidant MitoQ. CREB and its downstream mediators were examined by Western blotting analysis and quan-titative reverse transcription polymerase chain reaction. Results: CREB knockdown induced mitochondrial reactive oxygen species production and apoptosis in primary neurons whereas CREB overexpression brought the opposite effects. The TLE mice exhibited elevated oxidative stress and neuronal apoptosis with decreased expression of CREB and its downstream mediators including PKA, CaMKIV, arc, and c-fos. CREB inhibition exacerbated TLE-associated oxidative neuronal apoptosis and memory decline. MitoQ treatment restored the expression of CREB and its downstream mediators, and prevented TLE-associated oxidative neuronal damage and memory deficits aggravated by CREB inhibition. Conclusion: CREB plays a significant role in TLE-associated oxidative neuronal damage and memory impairment. This novel finding provides the evidence of the relationship between CREB and mitochondrial oxidative stress and cognitive dysfunction in epilepsy. Mitochondria-specific antioxidants such as MitoQ may alleviate TLE-associated cognitive dysfunction through activation of CREB and its downstream signaling pathways. © 2020 S. Karger AG, Basel Jihong Xing and Dongfeng Han contributed equally to the paper.

IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis

“…Activation of CREB is widely implicated in neuronal survival and has long been known to be important for the formation of memories. On the opposite, CREB signaling dysfunction is associated with several neurodegenerative diseases, including AD [31] and brain injury models [32]. These results confirm that IGF1Rs deficiency modulates the expression of key regulators of brain higher functions.…”

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

“…The increased mRNA expression of CREB-1 in the second hit PTZ group reflects the plausible role of CREB-1 in epilepsy as well as suggest that memory is impaired upon PTZ administration. Acknowledging the role of CREB in TLE associated cognitive decline (Xing et al, 2019), we hypothesize that CREB-1 plausibly contribute to the memory impairment in the second hit PTZ group as evidenced by an increased expression.…”

“…Anti-HMGB1 mAb Rescued Second Hit PTZ Induced Modulation in CREB-1 and NPY CREB is a transcription factor with established role in plasticity (Lonze and Ginty, 2002) and alteration in the level of CREB has been implicated in several psychiatric diseases (Carlezon et al, 2005). In addition to that, CREB has been well acknowledged for its role in memory formation, neuronal plasticity and long-term memory formation and regulates the genes (BDNF, C-FOS) that are crucial for memory formation (Xing et al, 2019). The increased mRNA expression of CREB-1 in the second hit PTZ group reflects the plausible role of CREB-1 in epilepsy as well as suggest that memory is impaired upon PTZ administration.…”

Antioxidants Targeting Mitochondrial Oxidative Stress: Promising Neuroprotectants for Epilepsy

“…Among these compounds, there are extensive publications of the neuroprotective effects of MitoQ against epileptic condition. It has demonstrated that treatment with MitoQ significantly rescues learning and memory deficits in pilocarpine-induced mice model of temporal lobe epilepsy via activation of cAMP response element-binding protein (CREB) [ 62 ]. The beneficial effect of MitoQ in the alleviation of memory decline is also found in Angelman syndrome [ 63 ], which is associated with epileptic pathology, and it is demonstrated that its therapeutic response is likely through reducing superoxide generation and suppressing neuronal apoptosis.…”