Depression is a severe life-threatening psychiatric disorder that is characterized by a lack of interest, loss of pleasure, impaired cognition, disturbed eating, sleeping, and sexual activity (Hammen, 2018; Monroe and Harkness, 2022). This serious illness is affecting approximately 280 million people worldwide (Ortega et al., 2022). Although the treatment for depression has been improved, the prevalence has not decreased yet (Antosik-Wójcińska et al., 2015; Sjöberg et al., 2017). Most commonly preferred antidepressants i.e. serotonin selective reuptake inhibitors (SSRIs) were developed many years ago and one-third of depressed patients have shown resistance to this drug treatment (Willner et al., 2014., Ionescu et al., 2015; Blier, 2016; Kverno and Mangano, 2021). Further, this treatment-prevalence paradox raises the question of the extensive research on depression for decades and necessitates more understanding of the underlying cellular and molecular mechanisms of this major depressive disorder which are poorly known.

Evidence from the preclinical and clinical studies including molecular, behavioral, and other studies, therefore, provide important insight that certain components of depression might result from chronic stress-induced neuroplastic changes in specific neural circuits which ultimately lead to phenotypic alterations observed in depression-like behavior (Duman et al., 2016; Liu et al., 2017). To adapt in response to any stressful stimuli or altered environmental conditions, neuroplasticity involves different mechanisms including synaptic remodeling which ultimately led to the functional modification of synapses and neural circuits. Imaging studies have demonstrated altered connectivity and network functioning in the brain samples from depressed patients (Savitz and Drevets, 2009; MacQueen and Frodl, 2011; Evans et al., 2008; Li et al., 2018). Several preclinical studies have also addressed significant alterations in neuronal morphology related to dendritic arbor simplification and dendritic spine loss in depression (Qiao et al., 2016; Uchida et al., 2018). Beyond the monoaminergic neurotransmission, elucidating the neural underpinnings of depression is the utmost need of an hour for the development of effective therapeutic drugs. Notably, these morphological changes observed under chronic stress exposure may be attributed to an altered signal transduction pathway which mainly targets the actin cytoskeleton.

Since last decades, there has been a growing interest in research investigations to elucidate the significance of the Rho/ROCK signaling pathway in the etiopathogenesis of various central nervous system (CNS) disorders including depression (Mueller et al., 2005; Kubo et al., 2008; Li et al., 2018; Mulherkar et al., 2017a); Román-Albasini et al. (2020). RhoA/ROCK signaling regulates actin cytoskeleton dynamics and modulates axon and dendritic spine growth (Martín-Cámara et al., 2021). The activation of ROCK leads to the phosphorylation of several central regulator proteins finally resulting in decreased cell growth, stress fiber formation, neurite retraction, induction of apoptosis, inhibition of autophagy, and cytoskeleton modulation. Stress is a precursor as well as a causative factor for the development of depression (Bali and Jaggi, 2014). Stress-induced Rho/ROCK activation promotes neuronal apoptosis and loss of neural processes and synapses to promote cerebral and cognitive dysfunction (Mulherkar et al., 2017; Román-Albasini et al., 2020; Jianjun et al., 2021). Furthermore, the pharmacological inhibition of the Rho/ROCK pathway has also proved to be efficacious in depression (Inan et al., 2015; García-Rojo et al., 2017), inflammatory and demyelinating diseases (Chen et al., 2017), Alzheimer's disease (Ruan et al., 2021), neuropathic pain (Tsukahara and Ueda, 2016) and sepsis-induced cerebral and cognitive injury (Jianjun et al., 2021). Intriguingly, pre-clinical studies have addressed that pretreatment with ROCK inhibitors notably affects the antidepressant-related pathways including the Brain-derived neurotrophic factor/tropomyosin receptor kinase (BDNF/TrkB) signaling, AKT, the mechanistic target of rapamycin complex 1 (mTORC1), myosin binding subunit (MYPT1) phosphorylation, N-Cadherin/β catenin signaling, mammalian homolog of Diaphanous (mDia) dependent presynaptic contractions. Thereby, suggesting the Rho/ROCK pathway is a putative target in depression like a serious illness.

The present review refine the prevailing contribution of this signaling pathway in depression and highlighted preclinical evidence for employing ROCK inhibitors as disease-modifying targets along with possible underlying mechanisms in stress-associated depression.