Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts

Tomov, Nikola; Surchev, L.; Wiedenmann, Clemens; Döbrössy, Máté; Nikkhah, Guido

doi:10.1016/j.expneurol.2019.04.013

Cited by 17 publications

(12 citation statements)

References 58 publications

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“…Since p38 MAPK inhibitor suppresses phagocytosis and MCP-1 synthesis in microglia [40,41], our findings indicate that roscovitine-induced inhibition of p38 MAPK activity may ameliorate MCP-1 synthesis and phagocytosis in activated microglia following SE. With respect to previous reports demonstrating anti-microglia-related neuroinflammatory effects of roscovitine in various harmful conditions, such as brain trauma, tissue graft and ischemia [13,14,42], our findings propose that inhibition of the association between CDK5 and the p38 MAPK signaling pathway may present a potential therapeutic target for diminishing neuroinflammatory responses.…”

Section: Discussionsupporting

confidence: 76%

“…Since CDK5 is one of the serine/threonine cyclin-dependent CDKs and roscovitine is a potential CDK5 inhibitor, the anti-inflammatory properties of roscovitine is relevant to the inhibition of microglia proliferation [14]. However, roscovitine also affects the activities of Cdc2, CDK2, CDK9 and protein kinase A [17,38,39].…”

Section: Discussionmentioning

confidence: 99%

“…MCP-1 is primarily credited with recruitment of macrophage populations to sites of expression mediated by its receptor, C-C motif chemokine receptor 2 (CCR2) [7,10,11]. Interestingly, roscovitine, a non-selective cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models [12,13,14]. Thus, it is likely that roscovitine may attenuate SE-induced monocyte infiltration by inhibiting microglia activation, which has not been examined, and this issue is the focus of the present study.…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Park

Choi

et al. 2019

Cells

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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.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kim

Park

Choi

et al. 2019

Cells

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“…Furthermore (R)-roscovitine was injected 24 h before MCA occlusion by intracerebroventricular infusion. Other publications also showed that (R)-roscovitine, decreased microglia activation or proliferation on other model of neurological injury ( Hilton et al , 2008 ; Kim et al , 2019 ; Tomov et al , 2019 ).…”

Section: Discussionmentioning

confidence: 80%

Principal component analysis, a useful tool to study cyclin-dependent kinase-inhibitor’s effect on cerebral ischaemia

Roy

Amara

Roux

et al. 2020

Brain Communications

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Stroke is a leading cause of acute death related in part to brain edema, blood brain barrier disruption and glial inflammation. A cyclin-dependant kinase inhibitor, (S)-roscovitine, was administered 90 minutes after onset on a model of rat focal cerebral ischemia. Brain swelling and Evans Blue tissue extravasation were quantified after Evans Blue injection. Combined tissue Evans Blue fluorescence and immunofluorescence of endothelial cells (RECA1), microglia (IB4) and astrocytes (GFAP) were analyzed. Using a Student’s t-test or Mann–Whitney test, (S)-roscovitine improved recovery by more than 50% compared to vehicle (Mann–Whitney, p < 0.001), decreased significantly brain swelling by 50% (t-test, p = 0.0128) mostly in the rostral part of the brain. Main analysis was therefore performed on rostral cut for immunofluorescence to maximize biological observations (cut B). Evans Blue fluorescence decreased in (S)-roscovitine group compared to vehicle (60%, t-test, p = 0.049) and was further supported by spectrophotometer analysis (Mann–Whitney, p = 0.0002) and Evans Blue macroscopic photonic analysis (t-test, p = 0.07). An increase of RECA-1 intensity was observed in the ischemic hemisphere compared to non-ischemic hemisphere. Further study showed, in the ischemic hemisphere that (S)-roscovitine treated group compared to vehicle, showed a decrease of: i) Endothelial RECA-1 intensity of about 20% globally, mainly located in the cortex (-28.5%, t-test, p = 0.03); ii) Microglia’s number by 55% (t-test, p = 0.006) and modulated reactive astrocytes through a trend toward less astrocytes number (15%, t-test, p = 0.05) and astrogliosis (21%, t-test, p = 0.076). To decipher the complex relationship of these components, we analyzed the 6 biological quantitative variables of our study by principal component analysis from immufluorescence studies of the same animals. Principal component analysis differentiated treated from non-treated animals on dimension 1 with negative values in the treated animals, and positive values in the non-treated animals. Interestingly, stroke recovery presented negative correlation with this dimension, while all other biological variables showed positive correlation. Dimensions 1 and 2 allowed the identification of two groups of co-varying variables: endothelial cells, microglia number and Evans Blue with positive values on both dimension, and astrocyte number, astrogliosis and brain swelling with negative values on dimension 2. This partition suggests different mechanisms. Correlation matrix analysis was concordant with Principal component analysis results. Because of its pleiotropic complex action on different elements of the NeuroVascular Unit response, (S)-roscovitine may represent an effective treatment against edema in stroke.

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“…CDK5 activity can also be inhibited by various pharmacological compounds. The earliest, and currently the most popular, inhibitors of CDK5 are the purine-based compounds olomoucine and roscovitine [61][62][63]. Though, due to the interaction of these purine-based compounds with the conserved ATP-binding pocket present in all members of the CDK family, both olomoucine and roscovitine are not selective inhibitors of CDK5 [53,64].…”

Section: Regulation Of Cdk5 Activitymentioning

confidence: 99%

CDK5: Key Regulator of Apoptosis and Cell Survival

Roufayel

Murshid

2019

Biomedicines

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The atypical cyclin-dependent kinase 5 (CDK5) is considered as a neuron-specific kinase that plays important roles in many cellular functions including cell motility and survival. The activation of CDK5 is dependent on interaction with its activator p35, p39, or p25. These activators share a CDK5-binding domain and form a tertiary structure similar to that of cyclins. Upon activation, CDK5/p35 complexes localize primarily in the plasma membrane, cytosol, and perinuclear region. Although other CDKs are activated by cyclins, binding of cyclin D and E showed no effect on CDK5 activation. However, it has been shown that CDK5 can be activated by cyclin I, which results in anti-apoptotic functions due to the increased expression of Bcl-2 family proteins. Treatment with the CDK5 inhibitor roscovitine sensitizes cells to heat-induced apoptosis and its phosphorylation, which results in prevention of the apoptotic protein functions. Here, we highlight the regulatory mechanisms of CDK5 and its roles in cellular processes such as gene regulation, cell survival, and apoptosis.

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Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts

Cited by 17 publications

References 58 publications

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

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

Principal component analysis, a useful tool to study cyclin-dependent kinase-inhibitor’s effect on cerebral ischaemia

CDK5: Key Regulator of Apoptosis and Cell Survival

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