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Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays important roles in cerebral ischemia. Previously we have found that L-F001, a novel fasudil-lipoic acid dimer with good pharmacokinetic characters has good neuroprotection against toxin-induced cell death in vitro and in vivo. Here, we investigated the protective effects of L-F001 against a Glutathione peroxidase 4 (GPX4) inhibitor Ras-selective lethality 3 (RSL3) -induced ferroptosis in HT22 cells. We performed MTT, Transmission Electron Microscope (TEM), Western blot, and immunofluorescence analyses to determine the protective effects of L-F001 treatment. RSL3 treatment significantly reduced HT22 cell viability and L-F001 significantly protected RSL3-induced cell death in a concentration-dependent manner and significantly attenuated Mitochondrial shrinkage observed by TEM. Meanwhile, L-F001 significantly decreased RSL3-induced ROS and lipid peroxidation levels in HT22 cells. Moreover L-F001could restore GPX4 and glutamate-cysteine ligase modifier subunit (GCLM) levels, and significantly deceased Cyclooxygenase (COX-2) levels to rescue the lipid peroxidation imbalance. In addition, FerroOrange fluorescent probe and Western blot analysis revealed that L-F001 treatment decreased the total number of intracellular Fe2+ and restore Ferritin heavy chain 1 (FTH1) level in RSL3-induced HT22 cells. Finally, L-F001 could reduce RSL3-induced c-Jun N-terminal kinase (JNK) activation, which might be a potential drug target for LF-001. Considering that L-F001 has a good anti-ferroptosis effect, our results showed that L-F001 might be a multi-target agent for the therapy of ferroptosis-related diseases, such as cerebral ischemia.

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Background: Chronic neuropathic pain often occurs with unclear mechanisms after brachial plexus root avulsion (BPRA) injuries. Emerging evidence suggests that the maladaptation of spinal glial glutamate transporter GLT-1 causes extracellular glutamate accumulation, contributing to central sensitization of chronic pain. Dexmedetomidine (DMET), an α2-adrenergic receptor (α2AR) agonist, widely used in the clinic as a sedative and analgesic drug, has been shown to inhibit glial activation. This study assessed DMET effects on BPRA induced pain and the possible involvement of GLT-1 regulation. Methods: The right C8 and T1 roots were avulsed to establish a lower trunk BPRA injury rat model and LPS-induced activation of rat primary cultured astrocytes. Then we used the molecular and behavioral assay combined with pharmacological manipulation to test the hypothesis that DMET attenuates the pain and neuroinflammation through restoring the GLT-1 function via PKA signaling.Results: The mechanical allodynia and thermal hyperalgesia appeared and reached the peak at 1-day post-injury (dpi) and persisted for at least 28 dpi. Notably, BPRA enhanced phosphorylated PKA levels, reduced GLT-1 expression, and caused an imbalance between anti- and proinflammatory cytokines in the affected spinal segments. Acute systemic or local DMET administration, at the un-sedative doses, demonstrated an analgesic effect. Moreover, a 3-days intrathecal DMET treatment ameliorated hyperalgesia and allodynia of BPRA injured rats by attenuating PKA phosphorylation, IL-1β, and IL-6, while restoring the levels of GLT-1, IL-4, and IL-10 in the spinal cord. Significantly, intrathecal administration of the selective PKA inhibitor H89 mimicked, but the PKA activator 8-Br-cAMP blocked DMET’s effects. Conclusion: Overall, these results suggest that PKA inactivation mediates DMET's analgesic effect for the pain induced by BPRA injury through the recovery of GLT-1 function.

Background Traumatic brain injury, one of the leading causes of death in adults under 40 years of age in the world, is frequently caused by mechanical shock, resulting in diffuse neuronal damage and long-term cognitive dysfunction. Many existing TBI animal models revival with expensive equipment or special room are needed or the processes of operations are complex and not easy to be widely used. Therefore, a simpler TBI model needs to be designed. Methods Our TBI model is an innovation of the modeling method through air guns shutting rubber bullets. A core facet is the application of our designed rubber bullet impact device. It could focus the hitting power to the fixed site of the brain, thus triggering a mild closed head injury. Moreover, the degree of damage can be adjusted by the times of shots. Results Our model induced blood-brain barrier leakage and diffused neuronal damage. Besides, it led to an increased level of Tau phosphorylation and resulted in cognitive dysfunction within several weeks post-injury. Conclusion Our TBI model is not only simple and time-saving but also can simulate mild brain injuries in clinical. It is suitable for exploring pathobiological mechanisms as well as a screening of potential therapies for TBI.