scholarly journals The matrix metalloproteinase inhibitor marimastat inhibits seizures in a model of kainic acid-induced status epilepticus

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Barbara Pijet ◽  
Anna Konopka ◽  
Emilia Rejmak ◽  
Marzena Stefaniuk ◽  
Danylo Khomiak ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Matrix Metalloproteinase ◽  
Kainic Acid ◽  
Blood Brain Barrier ◽  
Neuronal Cell ◽  
Subsequent Development ◽  
Brain Barrier ◽  
Neuronal Cultures ◽  
Metalloproteinase Inhibitor ◽  
Blood Brain

AbstractAn intra-hippocampus injection of kainic acid serves as a model of status epilepticus and the subsequent development of temporal lobe epilepsy. Matrix metalloproteinase-9 (MMP-9) is an enzyme that controls remodeling of the extracellular milieu under physiological and pathological conditions. In response to brain insult, MMP-9 contributes to pathological synaptic plasticity that may play a role in the progression of an epileptic condition. Marimastat is a metalloproteinase inhibitor that was tested in clinical trials of cancer. The present study assessed whether marimastat can impair the development of epilepsy. The inhibitory efficacy of marimastat was initially tested in neuronal cultures in vitro. As a marker substrate, we used nectin-3. Next, we investigated the blood–brain barrier penetration of marimastat using mass spectrometry and evaluated the therapeutic potential of marimastat against seizure outcomes. We found that marimastat inhibited the cleavage of nectin-3 in hippocampal neuronal cell cultures. Marimastat penetrated the blood–brain barrier and exerted an inhibitory effect on metalloproteinase activity in the brain. Finally, marimastat decreased some seizure parameters, such as seizure score and number, but did not directly affect status epilepticus. The long-term effects of marimastat were evident up to 6 weeks after kainic acid administration, in which marimastat still inhibited seizure duration.

Spatio-temporally restricted blood–brain barrier disruption after intra-amygdala kainic acid-induced status epilepticus in mice

2013 ◽  
Vol 103 (2-3) ◽  
pp. 167-179 ◽  
Author(s):  
Zuzanna Michalak ◽  
Takanori Sano ◽  
Tobias Engel ◽  
Suzanne F.C. Miller-Delaney ◽  
Mireille Lerner-Natoli ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Kainic Acid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

Increased serum matrix metalloproteinase-9 in neuromyelitis optica: Implication of disruption of blood–brain barrier

2011 ◽  
Vol 236 (1-2) ◽  
pp. 81-86 ◽  
Author(s):  
Takafumi Hosokawa ◽  
Hideto Nakajima ◽  
Yoshimitsu Doi ◽  
Masakazu Sugino ◽  
Fumiharu Kimura ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Blood Brain Barrier ◽  
Neuromyelitis Optica ◽  
Matrix Metalloproteinase 9 ◽  
Brain Barrier ◽  
Blood Brain ◽  
Metalloproteinase 9

scholarly journals Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage

2021 ◽  
Vol 16 (1) ◽  
pp. 845-855
Author(s):  
Huaxu Yu ◽  
Bin He ◽  
Xu Han ◽  
Ting Yan
Keyword(s):  
Kainic Acid ◽  
Blood Brain Barrier ◽  
Neuronal Damage ◽  
Brain Barrier ◽  
Protective Mechanism ◽  
Dependent Manner ◽  
Nissl Staining ◽  
Microglia Cell ◽  
Protein Levels ◽  
Blood Brain

Abstract Rufinamide (RUF) is a structurally unique anti-epileptic drug, but its protective mechanism against brain injury remains unclear. In the present study, we validated how the RUF protected mice with kainic acid (KA)-induced neuronal damage. To achieve that, a mouse epilepsy model was established by KA intraperitoneal injection. After Nissl staining, although there was a significant reduction in Nissl bodies in mice treated with KA, 40, 80, and 120 mg/kg, RUF significantly reduced KA-induced neuronal damage, in a dose-dependent manner. Among them, 120 mg/kg RUF was most pronounced. Immunohistochemistry (IHC) and western blot analysis showed that RUF inhibited the IBA-1 overexpression caused by KA to block microglia cell overactivation. Further, RUF treatment partially reversed neuroinflammatory cytokine (IL-1β, TNFα, HMGB1, and NLRP3) overexpression in mRNA and protein levels in KA mice. Moreover, although KA stimulation inhibited the expression of tight junctions, RUF treatment significantly upregulated expression of tight junction proteins (occludin and claudin 5) in both mRNA and protein levels in the brain tissues of KA mice. RUF inhibited the overactivation of microglia, suppressed the neuroinflammatory response, and reduced the destruction of blood–brain barrier, thereby alleviating the excitatory nerve damage of the KA-mice.

scholarly journals Gastrodia-Uncaria Water Extract Inhibits Endoplasmic Reticulum Stress and Matrix Metalloproteinase in Protecting against Cerebral Ischemia

2021 ◽  
Author(s):  
Angus Y Choi ◽  
Jia Wen Xian ◽  
Sum Yi Ma ◽  
Zhixiu Lin ◽  
Chun Wai Chan
Keyword(s):  
Endoplasmic Reticulum ◽  
Cerebral Ischemia ◽  
Endoplasmic Reticulum Stress ◽  
Blood Brain Barrier ◽  
Neuroprotective Effect ◽  
Water Extract ◽  
Neuronal Cell ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain

Stroke is the second leading cause of death in worldwide, in which cerebral ischemia accounts for 87% of all cases. The building up of endoplasmic reticulum stress in cerebral ischemia contributes to the disruption of blood brain barrier and neuronal cell death. The only FDA-approved drug, recombinant tissue plasminogen activator, is still of limited use due to the narrow window period and lack of neuroprotective effect. Therefore, it is necessary to explore alternative treatment on cerebral ischemia. Tianma-Gouteng decoction is a traditional Chinese Medicine prescription used to treat brain diseases in China. In this study, we investigated the neuroprotective effect of a water extract consisting of Gastrodia elata and Uncaria rhynchophylla, which are the two main herbs in the decoction. Cerebral ischemia was induced in rats using middle cerebral artery occlusion. GUW-treated rats have significantly reduced infarction volume and recovered neurological functions. The number of protein aggregates and caspase-12 positive cells were significantly inhibited. In vitro oxygen-glucose deprivation / reoxygenation stroke model demonstrated that the unfolded protein response proteins GRP78 and PDI were upregulated by GUW. Less ubiquitin puncta and normalized ubiquitin distribution indicated the reduction in endoplasmic reticulum stress. Furthermore, a lower Evan blue signal and MMPsense signal was observed, suggesting that GUW may preserve the blood brain barrier integrity through inhibiting MMP activity. Taken together, this suggested that GUW protected ischemic neurons and the blood brain barrier through inhibiting endoplasmic reticulum stress.

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