The Influence of Select Medications on Prospective Hemorrhage Risk in Patients with Spinal or Cerebral Cavernous Malformations.

BACKGROUND: Effects of select medications on hemorrhage risk in patients with cerebral or spinal cavernous malformations (CMs) are unknown. METHODS: From a single-institution prospective cohort of patients with CM (2015-2021), demographics, mode of clinical presentation, and radiographic data were collected. Follow-up was performed with electronic medical record review, in-person visits, and written surveys. Select medication use was ascertained from the time of CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, last follow-up, or death. Using Cox proportional hazards regression model, we assessed effects of antithrombotic agents, fish oil, selective serotonin reuptake inhibitors (SSRIs), vitamin E and D supplementation, statins, and beta blockers on prospective hemorrhage risk. RESULTS: The study included 364 patients with spinal or cerebral CM (58.0% female; 20.0% familial form; 42.3% presentation to medical attention owing to hemorrhage; 25.8% brainstem location). During a follow-up of 2018 patient-years, 103 prospective hemorrhages occurred. No studied medications increased the prospective CM hemorrhage risk. Antithrombotics, vitamin D supplementation, fish oil, and SSRI were associated with lower hemorrhage risk even after adjusting for age at diagnosis, hemorrhage at diagnosis, and brainstem location. CONCLUSIONS: Use of select medications with antithrombotic properties do not increase the risk of CM hemorrhage. Vitamin D supplementation, any antithrombotic agent, fish oil, and SSRI were associated with a lower prospective hemorrhage risk. Further studies should evaluate the mechanism of action and potential benefit of these select medications.

Phenothiazines Enhance the Hypothermic Preservation of Liver Grafts: A Pilot in Vitro Study.

In vitro liver conservation is an issue of ongoing critical importance in graft transplantation. In this study, we investigated the possibility of augmenting the standard pre-transplant liver conservation protocol (University of Wisconsin (UW) cold solution) with the phenothiazines chlorpromazine and promethazine. Livers from male Sprague-Dawley rats were preserved either in UW solution alone, or in UW solution plus either 2.4, 3.6, or 4.8 mg chlorpromazine and promethazine (C+P, 1:1). The extent of liver injury following preservation was determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, the ratio of AST/ALT, morphological changes as assessed by hematoxylin-eosin staining, apoptotic cell death as determined by ELISA, and by expression of the apoptotic regulatory proteins BAX and Bcl-2. Levels of glucose (GLU) and lactate dehydrogenase (LDH) in the preservation liquid were determined at 3, 12, and 24 h after incubation to assess glucose metabolism. Oxidative stress was assessed by levels of superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA), and inflammatory cytokine expression was evaluated with Western blotting. C+P augmentation induced significant reductions in ALT and AST activities; the AST/ALT ratio; as well as in cellular swelling, vacuolar degeneration, apoptosis, and BAX expression. These changes were associated with lowered levels of GLU and LDH; decreased expression of SOD, MDA, ROS, TNF-α, and IL-1ß; and increased expression of Bcl-2. We conclude that C+P augments hypothermic preservation of liver tissue by protecting hepatocytes from ischemia-induced oxidative stress and metabolic dysfunction. This result provides a basis for improvement of the current preservation strategy, and thus for the development of a more effective graft conservation method.

Aberrant trafficking of a Leu89Pro connexin32 mutant associated with X-linked dominant Charcot-Marie-Tooth disease.

OBJECTIVE: To determine the functional abnormalities of the Leu89Pro mutation in connexin32 (CX32), which we have previously reported is present within an X-linked dominant Charcot-Marie-Tooth disease family. In this family, male patients were moderately to severely affected. METHODS: We performed immunofluorescence to investigate whether the Leu89Pro CX32 protein was transported to the cell membrane in HeLa and Schwann cells. First, we constructed the eukaryotic express plasmids expressing CX32 (wild-type or Leu89Pro) and enhanced green fluorescent protein by the gene recombination technology. Then the recombinant plasmids were transiently transfected into communication-incompetent HeLa cells and human Schwann cells by the lipofectamine method. Later, we double-labeled cells for both CX32 and markers of the ER (calnexin) or the Golgi (58-kDa protein) at 24 h or 48 h. The images were collected using a Leica TCS SP5 II confocal microscope. RESULTS: The mutant CX32 protein was localized in the endoplasmic reticulum and failed to reach the cell membrane to form gap junctions. CONCLUSION: Our results indicated that the Leu89Pro substitution in the second transmembrane domain of CX32 disrupts the trafficking of the protein, inhibiting the assembly of CX32 gap junctions, which in turn may result in peripheral neuropathy. This functional abnormality may explain the moderate to severe phenotype seen in Leu89Pro patients, and as such represents a promising therapeutic target in the treatment of this subset of CMTX patients.

Progress in AQP Research and New Developments in Therapeutic Approaches to Ischemic and Hemorrhagic Stroke.

Cerebral edema often manifests after the development of cerebrovascular disease, particularly in the case of stroke, both ischemic and hemorrhagic. Without clinical intervention, the influx of water into brain tissues leads to increased intracranial pressure, cerebral herniation, and ultimately death. Strategies to manage the development of edema constitute a major unmet therapeutic need. However, despite its major clinical significance, the mechanisms underlying cerebral water transport and edema formation remain elusive. Aquaporins (AQPs) are a class of water channel proteins which have been implicated in the regulation of water homeostasis and cerebral edema formation, and thus represent a promising target for alleviating stroke-induced cerebral edema. This review examines the significance of relevant AQPs in stroke injury and subsequently explores neuroprotective strategies aimed at modulating AQP expression, with a particular focus on AQP4, the most abundant AQP in the central nervous system.

Pyruvate dehydrogenase complex in cerebral ischemia-reperfusion injury.

Pyruvate dehydrogenase (PDH) complex is a mitochondrial matrix enzyme that serves a critical role in the conversion of anaerobic to aerobic cerebral energy. The regulatory complexity of PDH, coupled with its significant influence in brain metabolism, underscores its susceptibility to, and significance in, ischemia-reperfusion injury. Here, we evaluate proposed mechanisms of PDH-mediated neurodysfunction in stroke, including oxidative stress, altered regulatory enzymatic control, and loss of PDH activity. We also describe the neuroprotective influence of antioxidants, dichloroacetate, acetyl-L-carnitine, and combined therapy with ethanol and normobaric oxygen, explained in relation to PDH modulation. Our review highlights the significance of PDH impairment in stroke injury through an understanding of the mechanisms by which it is modulated, as well as an exploration of neuroprotective strategies available to limit its impairment.