Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice.

BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.

Ruptured cerebral aneurysms in COVID-19 patients: A review of literature with case examples.

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 is responsible for over 83 million cases of infection and over 1.8 million deaths since the emergence of the COVID-19 pandemic. Because COVID-19 infection is associated with a devastating mortality rate and myriad complications, it is critical that clinicians better understand its pathophysiology to develop effective treatment. Cumulative evidence is suggestive of cerebral aneurysms being intertwined with the hyperinflammatory state and hypercytokinemia observed in severe COVID-19 infections. CASE DESCRIPTION: In case example 1, the patient presents with chills, a mild cough, and sore throat. The patient develops high-grade fever of 39.8° C, decreased oxygen saturation of 93% on room air, and an extensive spontaneous subarachnoid hemorrhage (SAH) in the basal cisterns from a ruptured left posterior communicating artery aneurysm. In case example 2, the patient presents with a positive PCR test for COVID-19 2 weeks prior with spontaneous SAH and found to have a large multilobulated bulbous ruptured aneurysm of the anterior communicating artery. Both patients' symptoms and high-grade fever are consistent with hypercytokinemia and a hyperinflammatory state, with elevated granulocyte colony-stimulating factor, inducible protein-10, monocyte chemoattractant protein-1, M1P1A, and tumor necrosis factor-α inflammatory mediators found to be elevated in COVID-19 intensive care unit admissions. CONCLUSION: COVID-19 effect on cerebral aneurysms requires future studies to clearly delineate correlation, however, hypercytokinemia and a hyperinflammatory state are strongly implicated to cause degenerative vascular changes that may predispose patients to cerebral aneurysm formation, change in size or morphology, and resultant aneurysm rupture.