Infralimbic cortex Rho-kinase inhibition causes antidepressant-like activity in rats

İnan, Salim Yalçın; Soner, Burak Cem; Şahin, Ayşe

doi:10.1016/j.pnpbp.2014.10.008

Cited by 17 publications

(6 citation statements)

References 72 publications

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“…We similarly find no effect of fasudil in adult stress-naïve mice, despite repeatedly detecting antidepressant-like actions in adolescent mice. In a separate study, the pan-ROCK inhibitor, Y-27632, had antidepressant-like effects in the FST in adult naïve male mice (Inan et al, 2015), but in this report, drugs were locally infused into the vmPFC rather than administered systemically, suggesting that the vmPFC is a key locus of antidepressant action. Given these and our own findings, we generated an shRNA against the ROCK2 isoform specifically, infusing it into the vmPFC prior to adolescence, anticipating maximal knockdown during adolescence.…”

Section: Selective Rock2 Inhibition In the Vmpfc Has Antidepressant-like Effectsmentioning

confidence: 77%

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice

Shapiro

Kietzman

Guo

et al. 2019

Neurobiology of Disease

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Adolescence represents a critical period of neurodevelopment, defined by structural and synaptic pruning within the prefrontal cortex. While characteristic of typical development, this structural instability may open a window of vulnerability to developing neuropsychiatric disorders, including depression. Thus, therapeutic interventions that support or expedite neural remodeling in adolescence may be advantageous. Here, we inhibited the neuronally-expressed cytoskeletal regulatory factor Rho-kinase (ROCK), focusing primarily on the clinically-viable ROCK inhibitor fasudil. ROCK inhibition had rapid antidepressant-like effects in adolescent mice, and its efficacy was comparable to ketamine and fluoxetine. It also modified levels of the antidepressant-related signaling factors, tropomyosin/tyrosine receptor kinase B and Akt, as well as the postsynaptic marker PSD-95, in the ventromedial prefrontal cortex (vmPFC). Meanwhile, adolescent-typical dendritic spine pruning on excitatory pyramidal neurons in the vmPFC was expedited. Further, vmPFC-specific shRNA-mediated reduction of ROCK2, the dominant ROCK isoform in the brain, had antidepressant-like consequences. We cautiously suggest that ROCK inhibitors may have therapeutic potential for adolescent-onset depression.

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Section: Selective Rock2 Inhibition In the Vmpfc Has Antidepressant-like Effectsmentioning

confidence: 77%

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice

Shapiro

Kietzman

Guo

et al. 2019

Neurobiology of Disease

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“…However, in our model, we do not know whether chronically administered Fasudil modifies noradrenergic neurotransmission. Furthermore, a recent study demonstrated that acute bilateral microinjection of the ROCK inhibitor Y-27632 (0.25 μg) into the infralimbic cortex of naïve rats increased active behavior during the FST (swimming and climbing) (Inan et al, 2015), similarly to drugs with dual effects on norepinephrine and serotonin transporters that extend the duration of both active behaviors (Detke et al, 1995, 1997). Thus, it seems plausible that drugs that do not share the same pharmacological profile, that is, antidepressant molecules and ROCK inhibitors, may converge into a common intracellular pathway that underlies the action of antidepressants.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the rise in phospho-MYPT1 levels was associated with the spine loss observed in secondary dendrites of CA1 pyramidal neurons of the hippocampus (Castaneda et al, 2015). Moreover, it has been demonstrated that bilateral infralimbic administration of Y-27632, a specific ROCK inhibitor, promotes antidepressant-like effects in naive rats that are similar to those produced by the antidepressant fluoxetine (Inan et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus

García-Rojo

Fresno

Vilches

et al. 2016

IJNPPY

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Background:Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss.Methods:Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed.Results:Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration.Conclusion:Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.

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“…Patients with epilepsy would also develop comorbidities like cognitive dysfunction and depression (Shultz et al 2015;Liu et al 2016). Y-27632 significantly reduced the immobility time of rats and increased swimming and climbing duration in the forced swimming test (Inan et al 2015). Therefore, Y-27632 demonstrates antidepressant-like activity in rats.…”

Section: Rho/rock Inhibitors In Epilepsy-related Comorbiditymentioning

confidence: 80%

The role of Rho/ROCK in epileptic seizure-related neuronal damage

2022

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Epilepsy is one of the most severe neurological disorders characterized by spontaneous recurrent seizures. Although more than two-thirds of patients can be cured with anti-epileptic drugs (AEDs), the rest one-third of epilepsy patients are resistant to AEDs. A series of studies have demonstrated Rho/Rho-associated kinase (ROCK) pathway might be involved in the pathogenesis of epilepsy in the recent twenty years. Several related pathway inhibitors of Rho/ROCK have been used in the treatment of epilepsy. We searched PubMed from Jan 1, 2000 to Dec 31, 2020, using the terms "epilepsy AND Rho AND ROCK" and "seizure AND Rho AND ROCK". We selected articles that characterized Rho/ROCK in animal models of epilepsy and patients. We then chose the most relevant research studies including in-vitro, in-vivo and clinical trials. The expression of Rho/ROCK could be a potential non-invasive biomarker to apply in treatment for patients with epilepsy. RhoA and ROCK show significant upregulation in the acute and chronic stage of epilepsy. ROCK inhibitors can reduce the epilepsy, epileptic seizure-related neuronal death and comorbidities. These findings demonstrate the novel development for diagnosis and treatment for patients with epilepsy. Rho/ROCK signaling pathway inhibitors may show more promising effects in epilepsy and related neurological diseases.

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Infralimbic cortex Rho-kinase inhibition causes antidepressant-like activity in rats

Cited by 17 publications

References 72 publications

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus

The role of Rho/ROCK in epileptic seizure-related neuronal damage

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