Post-treatment with the GLP-1 analogue liraglutide alleviate chronic inflammation and mitochondrial stress induced by Status epilepticus

Abstract

Glucagon-like peptide-1(GLP-1) is a growth factor that has neuroprotective and anti-inflammatory properties. The protease resistant GLP-1 analogue liraglutide has been shown to be neuroprotective in previous studies in animal models of Alzheimer's disease or Parkinson's disease. Status epilepticus (SE) is a complex disorder, involving many underlying pathological processes, including excitotoxic and chronic inflammatory events. The present pilot study aims to investigate whether liraglutide alleviates the chronic inflammation response and mitochondrial stress induced by SE in the lithium-pilocarpine animal model. We found that treatment with 25nmol/kg. i.p. once-daily after the induction of SE for 7 days reduced chronic inflammation as shown by reduced numbers of activated microglia and astrocytes, and reduced levels of TNF-α and IL-1ß in the hippocampus. The mitochondrial stress marker BAX was reduced and the survival factor Bcl-2 was enhanced by liraglutide. Blood glucose levels were not affected by liraglutide. We show for the first time that liraglutide can reduce the chronic inflammation and mitochondrial stress induced by SE, and the results suggest that GLP-1 receptor agonists such as liraglutide have restorative and protective effects in the brain after SE and could serve as a potential treatment.

The Glucagon-Like Peptide-1 Analogue Liraglutide Reduces Seizures Susceptibility, Cognition Dysfunction and Neuronal Apoptosis in a Mouse Model of Dravet Syndrome

“…The GLP-1 receptor (GLP-1R) is widely expressed in neurons of several brain subregions such as hypothalamus, hippocampus, and cortex (Cork et al, 2015;Yoshino et al, 2015), suggesting the GLP-1 signaling could modulate a variety of neuronal functions (Korol et al, 2015;Prashant et al, 2018). Indeed, it has been reported that GLP-1 analogues exert neuroprotective effects in mouse models of acute and chronic epilepsy (Koshal et al, 2018;Wang et al, 2018;Hussein et al, 2019). Previous studies have shown that different apoptosis signaling pathways including BCL-2 associated X protein (BAX)/B cell lymphoma 2 (BCL-2) proteins are involved in seizure-induced neuronal death (Guo et al, 2017;Rubio et al, 2019), and liraglutide treatment could reduce the expression of an apoptotic marker caspase-3 in the brain of a Pentylenetetrazole (PTZ)-induced kindled rat model (Hussein et al, 2019).…”

“…GLP-1 analogues can regulate mTOR expression via the AMPactivated protein kinase (AMPK) pathway (He et al, 2016;Zhang et al, 2017). Although several studies have shown the anticonvulsant potential of GLP-1 analogues (Koshal and Kumar, 2016;Wang et al, 2018;de Souza et al, 2019), the effect of liraglutide on the epileptogenesis and cognitive dysfunction in the DS mouse model has not been examined. In the present study, we investigated the possible anti-epileptic effect of liraglutide in Scn1a KO-induced epileptic mice and its potential effect on both Bcl-2 regulate apoptotic pathway and the mTOR pathway that are involved in epileptogenesis.…”

Treatment With Liraglutide Exerts Neuroprotection After Hypoxic–Ischemic Brain Injury in Neonatal Rats via the PI3K/AKT/GSK3β Pathway

“…Previous studies have indicated that the consequences of neonatal HI brain injury are not temporary, leading to neuropathies associated with the activation of neuroinflammatory processes. To our knowledge, liraglutide exerts a favorable anti-inflammatory effect in many animal models (McClean and Hölscher, 2014;Wang et al, 2018). The level of inflammatory cytokines at both the mRNA and protein levels can be used to evaluate the inflammatory response.…”

“…Numerous studies have suggested that liraglutide exerts neuroprotective effects against injury and diseases of the nervous system, such as Alzheimer's disease (McClean et al, 2011;McClean and Hölscher, 2014), Parkinson's disease (Aviles-Olmos et al, 2014;Badawi et al, 2017), acute ischemic stroke (Yang et al, 2016;Dong et al, 2017), and traumatic brain injury (DellaValle et al, 2014;Hakon et al, 2015). A recently published study indicated that liraglutide could alleviate chronic inflammation and mitochondrial stress induced by status epilepticus (Wang et al, 2018). Thus, far, the specific mechanism through which liraglutide exerts its effects on neonatal HI brain injury remains uncertain.…”

The GLP-1 analog, liraglutide prevents the increase of proinflammatory mediators in the hippocampus of male rat pups submitted to maternal perinatal food restriction

“…Also examination of placental epigenetic machinery revealed sex differences [ 52 , 53 ]. In mice, female placental tissue has higher levels of global DNA methylation compared to male’s placentas, which likely provide females additional protection from dynamic changes in gene expression promoted by environmental insults [ 54 ]. Furthermore, rodent brain development begins during gestation but mostly continues postnatally.…”