Roscovitine Attenuates Microglia Activation and Monocyte Infiltration via p38 MAPK Inhibition in the Rat Frontoparietal Cortex Following Status Epilepticus

Abstract

Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by brain-blood barrier. Following status epilepticus (SE, a prolonged seizure activity), microglia are rapidly activated and blood-derived monocytes that infiltrate the brain; therefore, the regulations of microglia activation and monocyte infiltration are one of the primary therapeutic strategies for inhibition of undesirable consequences from SE. Roscovitine, a potent (but not selective) cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models, although the underlying mechanisms have not been clarified. In the present study, roscovitine attenuated SE-induces monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC), accompanied by reducing expressions of monocyte chemotactic protein-1 (MCP-1) and lysosome-associated membrane protein 1 (LAMP1) in resident microglia, while it did not affect microglia transformation to amoeboid form. Furthermore, roscovitine ameliorated the up-regulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, but not nuclear factor-κB-S276 phosphorylation. Similar to roscovitine, SB202190, a p38 MAPK inhibitor, mitigated monocyte infiltration and microglial expressions of MCP-1 and LAMP1 in the FPC following SE. Therefore, these findings suggest for the first time that roscovitine may inhibit SE-induced neuroinflammation via regulating p38 MAPK-mediated microglial responses.

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

“…5C). Our results were consistent with previous studies [36][37][38] that p38 MAPK signaling was vital in activated microglia to release inflammatory cytokines, these findings also indirectly confirmed our hypothesis that activated microglial may lead to the apoptosis of photoreceptor by releasing inflammatory cytokines, which provides a plausible explanation about the mechanism between Aβ 1−42 induced microglia and photoreceptor apoptosis in AMD (Fig. 6).…”

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

“…Furthermore, with BIRB 796, the inhibitor of p38 MAPK phosphorylation, we found that the mRNA levels of in ammatory cytokines, including IL-1β, COX-2, TNF-a and iNOS, were decreased signi cantly under the treatment of BIRB 796 in microglia ( Figure 5C). Our results were consistent with previous studies [36][37][38] that p38 MAPK signaling was vital in activated microglia to release in ammatory cytokines, these ndings also indirectly con rmed our hypothesis that activated microglial may lead to the apoptosis of photoreceptor by releasing in ammatory cytokines, which provides a plausible explanation about the mechanism between Aβ 1-42 induced microglia and photoreceptor apoptosis in AMD ( Figure 6).…”

Blockade of 67-kDa Laminin Receptor Facilitates AQP4 Down-Regulation and BBB Disruption via ERK1/2-and p38 MAPK-Mediated PI3K/AKT Activations

“…Alzet 1007D osmotic pump contained (1) vehicle, (2) SB202190 (0.3 mg/mL), (3) wortmannin (0.1 nmol), (4) 3CAI (25 μM), and (5) U0126 (25 μM). In our previous studies [14,[16][17][18]30,31], each treatment did not show behavioral and neurological defects and could not change the seizure susceptibility and seizure severity in response to pilocarpine. Three days after surgery, this group was induced with SE by lithium chloride (LiCl)-pilocarpine.…”

“…Serum extravasation was measured, as previously described [14,17,18,31]. Aforementioned, sections were incubated in biotinylated rat IgG and ABC complex (Vector, #PK-6100, Burlingame, CA, USA, diluted 1:200).…”