| 1. |
- Aswendt, M., et al.
(author)
-
Reactive astrocytes prevent maladaptive plasticity after ischemic stroke
- 2022
-
In: Progress in Neurobiology. - : Elsevier BV. - 0301-0082. ; 209
-
Journal article (peer-reviewed)abstract
- Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP–/–Vim–/–). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP–/–Vim–/– mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes modulate recovery-promoting plasticity responses after ischemic stroke. © 2021
|
|
| 2. |
- Pekna, Marcela, 1966, et al.
(author)
-
Astrocyte Responses to Complement Peptide C3a are Highly Context-Dependent
- 2023
-
In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 48:4, s. 1233-1241
-
Journal article (peer-reviewed)abstract
- Astrocytes perform a range of homeostatic and regulatory tasks that are critical for normal functioning of the central nervous system. In response to an injury or disease, astrocytes undergo a pronounced transformation into a reactive state that involves changes in the expression of many genes and dramatically changes astrocyte morphology and functions. This astrocyte reactivity is highly dependent on the initiating insult and pathological context. C3a is a peptide generated by the proteolytic cleavage of the third complement component. C3a has been shown to exert neuroprotective effects, stimulate neural plasticity and promote astrocyte survival but can also contribute to synapse loss, Alzheimer's disease type neurodegeneration and blood-brain barrier dysfunction. To test the hypothesis that C3a elicits differential effects on astrocytes depending on their reactivity state, we measured the expression of Gfap, Nes, C3ar1, C3, Ngf, Tnf and Il1b in primary mouse cortical astrocytes after chemical ischemia, after exposure to lipopolysaccharide (LPS) as well as in control naive astrocytes. We found that C3a down-regulated the expression of Gfap, C3 and Nes in astrocytes after ischemia. Further, C3a increased the expression of Tnf and Il1b in naive astrocytes and the expression of Nes in astrocytes exposed to LPS but did not affect the expression of C3ar1 or Ngf. Jointly, these results provide the first evidence that the complement peptide C3a modulates the responses of astrocytes in a highly context-dependent manner.
|
|
| 3. |
- Pekna, Marcela, 1966, et al.
(author)
-
Targeting Complement C3a Receptor to Improve Outcome After Ischemic Brain Injury
- 2021
-
In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 46, s. 2626-2637
-
Journal article (peer-reviewed)abstract
- Ischemic stroke is a major cause of disability. No efficient therapy is currently available, except for the removal of the occluding blood clot during the first hours after symptom onset. Loss of function after stroke is due to cell death in the infarcted tissue, cell dysfunction in the peri-infarct region, as well as dysfunction and neurodegeneration in remote brain areas. Plasticity responses in spared brain regions are a major contributor to functional recovery, while secondary neurodegeneration in remote regions is associated with depression and impedes the long-term outcome after stroke. Hypoxic-ischemic encephalopathy due to birth asphyxia is the leading cause of neurological disability resulting from birth complications. Despite major progress in neonatal care, approximately 50% of survivors develop complications such as mental retardation, cerebral palsy or epilepsy. The C3a receptor (C3aR) is expressed by many cell types including neurons and glia. While there is a body of evidence for its deleterious effects in the acute phase after ischemic injury to the adult brain, C3aR signaling contributes to better outcome in the post-acute and chronic phase after ischemic stroke in adults and in the ischemic immature brain. Here we discuss recent insights into the novel roles of C3aR signaling in the ischemic brain with focus on the therapeutic opportunities of modulating C3aR activity to improve the outcome after ischemic stroke and birth asphyxia.
|
|
| 4. |
- Pekny, M., et al.
(author)
-
Neurofilament Light Chain (NfL) in Blood-A Biomarker Predicting Unfavourable Outcome in the Acute Phase and Improvement in the Late Phase after Stroke
- 2021
-
In: Cells. - : MDPI AG. - 2073-4409. ; 10:6
-
Journal article (peer-reviewed)abstract
- Increased sensitivity of methods assessing the levels of neurofilament light chain (NfL), a neuron-specific intermediate filament protein, in human plasma or serum, has in recent years led to a number of studies addressing the utility of monitoring NfL in the blood of stroke patients. In this review, we discuss that elevated blood NfL levels after stroke may reflect several different neurobiological processes. In the acute and post-acute phase after stroke, high blood levels of NfL are associated with poor clinical outcome, and later on, the blood levels of NfL positively correlate with secondary neurodegeneration as assessed by MRI. Interestingly, increased blood levels of NfL in individuals who survived stroke for more than 10 months were shown to predict functional improvement in the late phase after stroke. Whereas in the acute phase after stroke the injured axons are assumed to be the main source of blood NfL, synaptic turnover and secondary neurodegeneration could be major contributors to blood NfL levels in the late phase after stroke. Elevated blood NfL levels after stroke should therefore be interpreted with caution. More studies addressing the clinical utility of blood NfL assessment in stroke patients are needed before the inclusion of NfL in the clinical workout as a useful biomarker in both the acute and the chronic phase after stroke.
|
|
| 5. |
- Pozo-Rodrigálvarez, Andrea, et al.
(author)
-
C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
- 2021
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
-
Journal article (peer-reviewed)abstract
- Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis. Copyright © 2021 Pozo-Rodrigálvarez, Li, Stokowska, Wu, Dehm, Sourkova, Steinbusch, Mallard, Hagberg, Pekny and Pekna.
|
|
| 6. |
- Stokowska, Anna, et al.
(author)
-
Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
- 2023
-
In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:10
-
Journal article (peer-reviewed)abstract
- Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR-/-) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR-/- mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.
|
|
| 7. |
- Stokowska, Anna, et al.
(author)
-
Plasma neurofilament light chain levels predict improvement in late phase after stroke.
- 2021
-
In: European journal of neurology. - : Wiley. - 1468-1331 .- 1351-5101. ; 28:7, s. 2218-2228
-
Journal article (peer-reviewed)abstract
- Although functional recovery is most pronounced in the first 6 months after stroke, improvement is possible also in the late phase. We explored the value of plasma neurofilament light chain (NfL), a biomarker of axonal injury and secondary neurodegeneration, for the prediction of functional improvement in late phase after stroke.We measured baseline plasma NfL levels in 115 participants of a trial on the efficacy of multimodal rehabilitation in late phase after stroke. We determined the association between NfL levels, impairment in balance, gait and cognitive domains, and improvement 3 and 9 months later.Plasma NfL levels were associated with the degree of impairment in all three domains. Individuals with meaningful improvement in balance and gait capacity had higher plasma NfL levels compared with non-improvers (P=0.001 and P=0.018, respectively). Higher NfL levels were associated with improvement in balance (OR 2.34, CI: 1.35-4.27, P=0.004) and gait (OR 2.27, CI: 1.25-4.32, P=0.009). Elevated plasma NfL levels showed a positive predictive value for cognitive improvement, and this effect was specific for the intervention targeting the cognitive domain. The association of NfL levels with cognitive improvement withstood correction for baseline impairment, age and total years of schooling (OR 7.54, CI: 1.52-45.66, P=0.018).In addition to its established role as a biomarker in the acute phase, elevated circulating NfL levels may predict functional improvement in late phase after stroke. Our results should prompt further studies into the use of plasma NfL as a biomarker in late phase after stroke.
|
|
