3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Cerebral-Hemorrhage

Tyrosine kinase Fyn is a member of the Src kinase family, which is involved in neuroinflammation, apoptosis, and oxidative stress. Its role in intracerebral hemorrhage (ICH) is not fully understood. In this study, we found that Fyn was significantly elevated in human brain tissue after ICH. Accordingly, we investigated the role of Fyn in a rat ICH model, which was constructed by injecting blood into the right basal ganglia. In this model, Fyn expression was significantly upregulated in brain tissue adjacent to the hematoma. SiRNA-induced Fyn knockdown was neuroprotective for secondary cerebral damage, as demonstrated by reduced brain edema, suppression of the modified neurological severity score, and mitigation of blood-brain barrier permeability and neuronal damage. Fyn downregulation reduced apoptosis following ICH, as indicated by downregulation of apoptosis-related proteins AIF, Cyt.c, caspase 3, and Bax; upregulation of anti-apoptosis-related protein Bcl-2; and decreased tunnel staining. Mdivi-1, a Drp1 inhibitor, reversed Fyn overexpression induced pro-apoptosis. However, Fyn did not significantly affect inflammation-related proteins NF-κB, TNF-α, caspase 1, MPO, IL-1β, or IL-18 after ICH. Fyn activated Drp1 signaling by phosphorylating Drp1 at serine 616, which increased apoptosis after ICH in rats. This study clarifies the relationship between Fyn, apoptosis, and inflammation following ICH and provides a new strategy for exploring the prevention and treatment of ICH. KEY MESSAGES: ICH induced an increase in Fyn expression in human and rat cerebral tissues. Knockdown of Fyn prevented cerebral damage following ICH. Inhibition of Fyn had no significant effects on inflammatory responses. However, the downregulation of Fyn exerted neuroprotective effects on apoptosis. Fyn perturbed ICH-induced cell apoptosis by interacting with and phosphorylating (Ser616) Drp1 in a rat ICH model.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Blood-Brain Barrier; Brain; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Down-Regulation; Dynamins; Gene Knockdown Techniques; Humans; Male; Nerve Tissue Proteins; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-fyn; Quinazolinones; Rats; Rats, Sprague-Dawley; RNA Interference; RNA, Small Interfering; Signal Transduction; Specific Pathogen-Free Organisms

Intracerebral hemorrhage (ICH) is a serious public health problem with high rates of death and disability. The neuroprotective effect of Growth Differentiation Factor 11 (GDF11) in ICH has been initially proved by our previous study. Oxidative stress (OS) plays crucial roles in mediating subsequent damage of ICH. However, whether and how mitochondrial dynamic events and function participated in ICH pathophysiology, and how mitochondrial function and OS interreacted in the neuroprotective process of GDF11 in ICH remains unclarified. Based on the rat model of ICH and in vitro cell model, we demonstrated that GDF11 could alleviate ICH induced neurological deficits, brain edema, OS status, neuronal apoptosis and inflammatory reaction. In addition, mitochondrial functional and structural impairments were obviously restored by GDF11. Treatment with antioxidant protected against erythrocyte homogenate (EH) induced cell injury by restoring OS status and mitochondrial fusion fission imbalance, which was similar to the effect of GDF11 treatment. Further, inhibition of mitochondrial division with Mdivi-1 attenuated mitochondrial functional defects and neuronal damages. In conclusion, our results for the first time proposed that GDF11 protected the post-ICH secondary injury by suppressing the feedback loop between mitochondrial ROS production and mitochondrial dynamic alteration, resulting in attenuated mitochondrial function and amelioration of neural damage.

Topics: Animals; Antioxidants; Apoptosis; Brain Injuries; Cerebral Hemorrhage; Disease Models, Animal; Enzyme Activation; Growth Differentiation Factors; Humans; Inflammation; L-Lactate Dehydrogenase; Male; Mitochondrial Dynamics; Neurons; Neuroprotective Agents; Oxidative Stress; Quinazolinones; Rats; Reactive Oxygen Species