Spatiotemporal Cofilin Signaling, Microglial Activation, Neuroinflammation, and Cognitive Impairment Following Hemorrhagic Brain Injury.
Daniyah A AlmarghalaniXiaojin ShaRobert E MrakZahoor A ShahPublished in: Cells (2023)
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.
Keyphrases
- cognitive impairment
- brain injury
- inflammatory response
- transforming growth factor
- lipopolysaccharide induced
- neuropathic pain
- lps induced
- traumatic brain injury
- endothelial cells
- healthcare
- cerebral ischemia
- mouse model
- high fat diet induced
- coronary artery
- skeletal muscle
- rheumatoid arthritis
- end stage renal disease
- spinal cord injury
- nitric oxide synthase
- heart failure
- poor prognosis
- metabolic syndrome
- chronic kidney disease
- protein protein
- cardiovascular events
- blood brain barrier
- type diabetes
- high resolution
- left ventricular
- signaling pathway
- social media
- reactive oxygen species
- pulmonary artery
- coronary artery disease
- amino acid
- mental health
- ejection fraction
- nitric oxide
- insulin resistance
- heat stress
- cardiovascular disease