Exendin-4 Plays a Protective Role in a Rat Model of Spinal Cord Injury Through SERCA2

Abstract

Background/Aims: Current therapies for spinal cord injury (SCI) have limited efficacy, and identifying a therapeutic target is a pressing need. Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) plays an important role in regulating calcium homeostasis, which has been shown to inhibit apoptosis. Exendin-4 has been shown to inhibit the apoptosis of nerve cells in SCI, which can also improve SERCA2 expression. In this study, we sought to determine whether exendin-4 plays a protective role in a rat model of SCI via SERCA2. Methods: To investigate the effects of exendin-4 on SCI, a rat model of SCI was induced by a modified version of Allen’s method. Spinal cord tissue sections from rats and western blot analysis were used to examine SERCA2 expression after treatment with the long-acting glucagon-like peptide 1 receptor exendin-4 or the SERCA2 antagonist 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CE). Locomotor function was evaluated using the Basso Beattie Bresnahan locomotor rating scale and slanting board test. Results: Cell apoptosis was increased with CE treatment and decreased with exendin-4 treatment. Upregulation of SERCA2 in female rats with SCI resulted in an improvement of motor function scores and histological changes. Conclusion: These findings suggest that exendin-4 plays a protective role in a rat model of SCI through SERCA2 via inhibition of apoptosis. Existing drugs targeting SERCA2 may be an effective therapeutic strategy for the treatment of SCI.

Pharmacokinetics and efficacy of PT302, a sustained-release Exenatide formulation, in a murine model of mild traumatic brain injury

“…The activation of the GLP-1R on neurons generates potent neuro-trophic and neuroprotective actions across cellular and animal models of brain injury and neurodegeneration (Athauda and Foltynie, 2016, 2018; Hölscher, 2018; Kim et al, 2017; Li et al, 2016; Salcedo et al, 2012; Verma et al, 2018), which include multiple models of TBI (Eakin et al, 2013; Greig et al, 2014; Hakon et al, 2015; Rachmany et al, 2017; Rachmany et al, 2013; Tweedie et al, 2016a; Tweedie et al, (2013), spinal cord injury (Sun et al, 2018), stroke and subarachnoid hemorrhage (Li et al, 2009; Xie et al, 2018) as well as degenerative disorders such as AD, PD, multiple system atrophy, ALS, Huntington’s disease and peripheral neuropathy (Athauda and Foltynie, 2018; Athauda and Foltynie, 2016; Bassil et al, 2017; Bertilsson et al, 2008; Harkavyi and Whitton, 2010; Hölscher, 2018; Kim et al, 2017; Li et al, 2012; Li et al, 2010a; Li et al, 2009; Li et al, 2016; Salcedo et al, 2012). Because of numerous key measures of improved outcome cross-validated between such animal models as well as across independent laboratories at different institutions, interest in the evaluation of incretin mimetics in humans with neurodegenerative disorders has grown, and has spawned clinical trials in PD and AD [(Athauda et al, 2017; Athauda and Foltynie, 2018; Aviles-Olmos et al, 2013, 2014; Gejl et al, 2016); and ongoing clinical trials: NCT03456687, NCT02953665, NCT01843075, NCT01469351], as well as a growing interest in other neurological disorders including TBI (Greig et al, 2014).…”

The GLP-1 receptor agonist exenatide improves recovery from spinal cord injury by inducing macrophage polarization toward the M2 phenotype

“…Compared to the control group, the exenatide group showed significantly higher Arginase 1 mRNA levels (A) and higher CD163 levels (B) on day 3 after injury, and significantly higher CD206 levels on days 1 and 3 after injury (C). function after SCI (Li H et al, 2015;Li Y et al, 2015;Li et al, 2016;Sun et al, 2018). Many possible mechanisms for the neuroprotective effects of GLP-1 receptor agonists have been reported.…”

“…Although GLP-1 receptor agonists first came to prominence as a treatment for type-2 diabetes ( Holst, 2004 ; Baggio and Drucker, 2007 ), similar protective effects have been confirmed on cells in the central nervous system, with reports describing the beneficial effects of GLP-1 receptor agonists in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease ( Perry and Greig, 2002 ; Greig et al, 2004 ; Harkavyi et al, 2008 ; Aviles-Olmos et al, 2013 ; Ghasemi et al, 2013 ; Qiu et al, 2016 ; Kong et al, 2023 ; Koshatwar et al, 2023 ), the reduction of ischemic damage and maintenance of the blood–brain barrier after cerebral infarction ( Li et al, 2009 ; Lee et al, 2011 ; Darsalia et al, 2014 ; Shan et al, 2019 ), and the recovery of motor function after SCI ( Li H et al, 2015 ; Li Y et al, 2015 ; Li et al, 2016 ; Sun et al, 2018 ).…”

Exendin-4 as a Versatile Therapeutic Agent for the Amelioration of Diabetic Changes

“… 54 The administration of Ex-4 was shown to promote SERCA expression through activation of PKA/cAMP signaling pathways and subsequently leads to inhibition apoptosis after the onset of spinal cord injury. 55 The levels of pro-apoptotic effectors such as Bax, Caspase-3 and cytochrome C are decreased while the expression of Bcl-2. 56 Therefore, it seems that the application of Ex-4 could reverse the detrimental effects of Ex-4 on acute CNS pathologies.…”