|
Stroke
|
Acute brain injury leading to long-term
disability. Few therapeutic options
available
Male gender, atherosclerosis,
autoimmune disease, infection, and
inflammation increase the risk [98,99]
High circulating Dkk1 levels in patients
after acute ischemic stroke [100] |
Dkk1 upregulation in cerebral ischemia rodent model [5] Dkk1 counteracts E2-induced Wnt/β-catenin signaling and postischemia protection [86] Wnt1 reduces cerebral infarction, improves neurological recovery [79] GSK-3β inhibitors mitigate neuron death [5,76] HIF-1αa via Wnt is proneurogenic in stroke [101] Lentivirus expressing Wnt3a injection in SVZ and Stra induce functional recovery [16]
|
Neuroinflammation plays a causative role in ischemic stroke injury believed to trigger the progressive growth of the lesion [99] Mitigation of inflammation promotes neurogenesis [65] GSK-3β inhibition post-stroke mitigates inflammation [76,78] EEN mitigates microglia proinflammatory phenotype [96] Wnt1 repress inflammatory microglial activation [79,80] Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats [93]
|
Traumatic
brain injury (TBI)
|
Acute brain injury resulting in delayed
cell death and altered neuronal
architecture
Gender differences in immune,
inflammatory, and cell death
responses [102]
Unbalanced pro/anti-inflammatory
cytokines/chemokines [103] |
β-catenin signaling in proliferating NG2+ progenitor cells of the cortex [67] Wnt5a/Fzd2 is increased in ipsilateral hippocampus [68] Lrp6, β-catenin, and GSK-3β are rapidly and transiently affected after TBI [75] Neurogenesis is increased in hippocampus [104] Lithium inhibits GSK-3β, ameliorates neurodegeneration, and improves learning and memory [75,77]
|
Blood–brain barrier (BBB) breakdown, invasion of immune cells, and activation of glial cell proinflammatory mediators contribute to secondary injury and impair recovery [103] GSK-3β inhibitors mitigate inflammation [77] Ibuprofen attenuates inflammation and allows formation of migratory neuroblasts from grafted stem cells [94] EEN ameliorates behavioral outcome [105]
|
Parkinson’s
disease (PD)
|
Chronic degeneration of DA pigmented
neurons in the SNpca, Lewy bodies,
depletion of striatal DA, and astrogliosis.
No cure available
Parkin [57], LRRK2 [14,106], GSK-3β
[107], Nurr1 [108], gene mutations,
aging, male gender, GR-deficiencya,
E2-deficiency, and environmental
toxins augment the risk [87] |
Wnt1 expression increases after MPTP injury [8,17] Wnt1 promotes DA neuroprotection in vivo and in vitro [8,17] Dkk1 i.c.v. in intact SNpc promotes DA neuronal death, decreases β-catenin, and upregulates GSK-3β [17] GSK-3β inhibition promotes DA neuroprotection [8,17,107,109,110] GSK-β antagonists promote neurogenesis in SVZ [10,52]
|
Innate glial and adaptive reactions are key responses in PD pathology [11,87] NO antagonists, NO NSAIDs, anti-oxidant increase Wnt/β-catenin signaling [10,15] MPTP upregulates Wnt1 in VM astrocytes, in vivo/in vitro [8,17] Chemokine-activated astrocytes express Wnt1 [8] Astrocyte-derived Wnt1 promote neurogenesis from adult SVZ and DA neurogenesis from VM NPCs [8,10] Wnt1 is reduced in aged VM astrocyte associated with microglia overactivation [8] NO-flurbiprofen and GSK-3β inhibitors reverse Wnt/β-catenin inhibition in NPCs [10]
|
