This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer’s, Parkinson’s, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington’s) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin’s involvement is underscored by its impact on pathological hallmarks like Aβ plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson’s disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin’s association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington’s disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer’s, Parkinson’s, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.

Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-β TGF-β, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.

Microglial activation and failure of the antioxidant defense mechanisms are major hallmarks in different brain injuries, particularly traumatic brain injury (TBI). Cofilin is a cytoskeleton-associated protein involved in actin binding and severing. In our previous studies, we identified the putative role of cofilin in mediating microglial activation and apoptosis in ischemic and hemorrhagic conditions. Others have highlighted the involvement of cofilin in ROS production and the resultant neuronal death; however, more studies are needed to delineate the role of cofilin in oxidative stress conditions. The present study aims to investigate the cellular and molecular effects of cofilin in TBI using both in vitro and in vivo models as well as the first-in-class small-molecule cofilin inhibitor (CI). An in vitro H₂O₂-induced oxidative stress model was used in two different types of cells, human neuroblastoma (SH-SY5Y) and microglia (HMC3), along with an in vivo controlled cortical impact model of TBI. Our results show that treatment with H₂O₂ increases the expression of cofilin and slingshot-1 (SSH-1), an upstream regulator of cofilin, in microglial cells, which was significantly reduced in the CI-treated group. Cofilin inhibition significantly attenuated H₂O₂-induced microglial activation by reducing the release of proinflammatory mediators. Furthermore, we demonstrate that CI protects against H₂O₂-induced ROS accumulation and neuronal cytotoxicity, activates the AKT signaling pathway by increasing its phosphorylation, and modulates mitochondrial-related apoptogenic factors. The expression of NF-E2-related factor 2 (Nrf2) and its associated antioxidant enzymes were also increased in CI-treated SY-SY5Y. In the mice model of TBI, CI significantly activated the Nrf2 and reduced the expression of oxidative/nitrosative stress markers at the protein and gene levels. Together, our data suggest that cofilin inhibition provides a neuroprotective effect in in vitro and in vivo TBI mice models by inhibiting oxidative stress and inflammatory responses, the pivotal mechanisms involved in TBI-induced brain damage.

Neuroinflammation after intracerebral hemorrhage (ICH) is a crucial factor that determines the extent of the injury. Cofilin is a cytoskeleton-associated protein that drives neuroinflammation and microglia activation. A novel cofilin inhibitor (CI) synthesized and developed in our lab has turned out to be a potential therapeutic agent for targeting cofilin-mediated neuroinflammation in an in vitro model of ICH and traumatic brain injury. The current study aims to examine the therapeutic potential of CI in a mouse collagenase model of ICH and examine the neurobehavioral outcomes and its mechanism of action. Male mice were subjected to intrastriatal collagenase injection to induce ICH, and sham mice received needle insertion. Various concentrations (25, 50, and 100 mg/kg) of CI were administered to different cohorts of the animals as a single intravenous injection 3 h following ICH and intraperitoneally every 12 h for 3 days. The animals were tested for neurobehavioral parameters for up to 7 days and sacrificed to collect brains for hematoma volume measurement, Western blotting, and immunohistochemistry. Blood was collected for cofilin, TNF-α, and IL-1β assessments. The results indicated that 50 mg/kg CI improved neurological outcomes, reversed post-stroke cognitive impairment, accelerated hematoma resolution, mitigated cofilin rods/aggregates, and reduced microglial and astrocyte activation in mice with ICH. Microglia morphological analysis demonstrated that CI restored the homeostasis ramification pattern of microglia in mice treated with CI. CI suppressed endoplasmic reticulum stress-related neuroinflammation by inhibiting inflammasomes and cell death signaling pathways. We also showed that CI prevented synaptic loss by reviving the pre- and post-synaptic markers. Our results unveil a novel therapeutic approach to treating ICH and open a window for using CI in clinical practice.

Background: Sickle cell disease (SCD) is a genetic hematological disorder associated with significant mortality and a range of complex complications that manifest differently across various age groups. Methods: This study aimed to evaluate the demographic, clinical, and laboratory characteristics of SCD patients in Taif City, Saudi Arabia, with a focus on variations among children, adolescents, adults, and middle-aged individuals. A multicenter retrospective cohort study included 129 patients with confirmed diagnosis of SCD between January 2018 to October 2023 and divided into 4 cohorts. The analysis compared hospital stay durations, admission rates, SCD complications, and medication usage. Results: Among the participants, 35 were children (27%), 18 adolescents (14%), 63 adults (49%), and 13 middle-aged individuals (10%). Clinical complications as splenic disease in children (34.3%) were more frequent compared to adolescents (5.6%) and adults (4.8%). Additionally, chronic kidney disease was more prevalent in middle-aged patients (15.4%). Pain was reported in 65.1% of patients, with vascular occlusive crises occurring in 41.1%. Treatment adherence varied, with children showing higher penicillin use (74.3%), while opioid usage was greater in middle-aged patients (76.9%). Conclusions: The findings underscore the necessity for age-specific management strategies in SCD. Further research with larger populations is suggested to enhance the understanding of disease progression and treatment efficacy across different age groups.