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Monoacylglycerol Lipase Inhibition Using ABX-1431 Attenuates Cerebral Ischaemia Early After Traumatic Brain Injury
Denis E Bragin1,2, Olga A Bragina3, Dan P Covey3
1Lovelace Biomedical Research Institute, Albuquerque, NM, USA. dbragin@lrri.org.
Advances in Experimental Medicine and Biology
|October 14, 2024
Summary
Monoacylglycerol lipase (MAGL) inhibition with ABX-1431 effectively reduces cerebral ischemia following traumatic brain injury (TBI). This treatment mitigates microvascular dysfunction and tissue hypoxia, promoting better outcomes after TBI.
Area of Science:
- Neuroscience
- Traumatic Brain Injury Research
- Pharmacology
Background:
- Traumatic brain injury (TBI) pathology includes reduced cerebral blood flow (CBF), worsening secondary injury and hindering recovery.
- Endogenous cannabinoid system (eCBs) signaling, particularly via 2-arachidonoylglycerol (2-AG) acting on cannabinoid receptor type 1, plays a role in neuroprotection and anti-inflammatory effects post-TBI.
- Monoacylglycerol lipase (MAGL) regulates 2-AG levels, making its inhibition a potential therapeutic strategy for TBI.
Purpose of the Study:
- To evaluate the efficacy of potentiating 2-AG signaling through MAGL inhibition using ABX-1431 immediately after TBI.
- To investigate the impact of MAGL inhibition on cerebral blood flow, microcirculation, and tissue oxygenation following closed-head injury (CHI).
Main Methods:
- Male C57BL/6 J mice underwent a modified moderate Shohami weight-drop closed-head injury (CHI).
- ABX-1431 (5 mg/kg) or vehicle was administered intraperitoneally 30 minutes post-CHI.
- Cerebral blood flow (CBF) was mapped using laser speckle contrast imaging (LSCI).
- Cerebral microcirculation, mitochondrial respiration, and tissue oxygen supply were monitored using in-vivo two-photon laser scanning microscopy (2PLSM) and NADH autofluorescence.
Main Results:
- CHI induced a significant decrease in regional CBF, arteriole diameters (vasospasm), blood flow volume, and capillary flow velocity, leading to microthrombosis and tissue hypoxia.
- ABX-1431 treatment, administered 30 minutes post-CHI, significantly mitigated the development of microvascular dysfunction, capillary microthrombosis, and tissue hypoxia compared to the vehicle group (p < 0.05).
- The protective effects were observed starting 1 hour after CHI, indicating early intervention benefits.
Conclusions:
- MAGL inhibition by ABX-1431 effectively attenuates early cerebral ischemia and microvascular dysfunction following TBI.
- The observed cerebrovascular relaxation mediated by 2-AG suggests a potential dual mechanism involving smooth muscle contractility and endothelial vasodilator release.
- Targeting the eCB system via MAGL inhibition presents a promising therapeutic strategy for improving outcomes in traumatic brain injury.
