Ann N Y Acad Sci. Jun; Neurogenesis and neuroprotection in the adult brain. A putative role for 5-lipoxygenase? Manev H(1), Uz T, Manev R. Regen Med. ;10(2) doi: /rme Epub Dec 8. Valproic acid-mediated neuroprotection and neurogenesis after spinal cord injury . Neuroprotection and enhanced neurogenesis by extract from the tropical plant Knema laurina after inflammatory damage in living brain tissue.
and neurogenesis Neuroprotection
Although previous studies have demonstrated a role for Npas4 in the protection of neurons against several types of neurodegenerative insult, little is known about its neuroprotective role in response to ischaemic brain injury. Chapter 2 demonstrates that Npas4 has a neuroprotective role in ischaemia since Npas4 deficiency increased the susceptibility of cultured neurons to cell death by oxygen and glucose deprivation and aggravated the severity of brain injury after photochemical stroke in mice.
Furthermore, ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death following focal cerebral ischaemia.
These findings suggest that the mechanism underlying the in vivo protective effect of Npas4 after ischaemic insult could be due to its capacity to limit progressive neurodegeneration and neuroinflammation. Npas4 is a brain-specific transcription factor whose expression has been reported to be enriched in neurogenic regions of the brain, implicating a role for Npas4 in neurogenesis. Using two independent in vitro models of neurogenesis, we recently demonstrated that Npas4 expression is dynamic and highly regulated during neural differentiation of embryonic stem cells ESCs.
However, the factors responsible for regulating Npas4 expression during this process remain to be elucidated. Given that increasing evidence suggests that microRNAs miRNAs play central roles in both embryonic and adult neurogenesis, we reasoned that miRNAs are good candidates for the regulation of Npas4 expression during neural differentiation of ESCs. Chapter 3 provides insight into the underlying mechanisms by which Npas4 expression is regulated during neural differentiation of mouse ESCs mESCs.
The proposed book is unique because it gives a comprehensive account of the neuroprotective and neurogenic effects of steroid and polypeptide hormones. Furthermore, new pharmacological approaches for treatment of neurodegenerative conditions are presented, based on the neuroprotective and neurogenic properties of natural and synthetic hormones.
About the Author Dr. His research focuses on the role of hormonal micro-environment in neurodegenerative diseases and the development of micromolecular neuroprotective and neurogenic compounds. Synthia Mellon was awarded the Richard E. She has been a member of numerous Editorial Boards and review committees, and has served as a reviewer for numerous scientific journals.
Her research focuses on the developmental regulation of steroid hormone production, and the role of neurosteroids in developmental and neurodegenerative disorders of the nervous system and in the etiology of neuropsychiatric disease.
In the cerebral cortical region salvaged by VEGF i. Data shown are representative of findings from at least four animals per experiment. Note that a higher neurological grade in b denotes more severely impaired function.
VEGF and neurogenesis in ischemic brain. We showed previously that after VEGF infusion, BrdU incorporation in the two principal neuroproliferative zones of the mammalian brain — the subgranular zone SGZ of the hippocampal DG and the rostral subventricular zone SVZ — colocalizes with the neuronal lineage marker, Dcx In each case, the number of BrdU-labeled cells was 1.
The magnitude of this difference ranged from 2. These findings indicate that a the neuroproliferative effects of ischemia and VEGF are not additive, suggesting that the effect of ischemia may be mediated by VEGF or by another factor that activates the same signal transduction pathways activated by VEGF; and b in contrast to the increase in BrdU labeling in DG and SVZ induced by VEGF in nonischemic brains at shorter intervals 26 , the delayed emergence of the effect observed at 28 days suggests that it is likely to involve increased survival rather than increased proliferation of VEGF-stimulated precursors.
Scheme for quantifying postischemic neurogenesis in the rat brain. MCAO was induced on day 0, VEGF given by the intracerebroventricular route as shown in upper left and BrdU given by the intraperitoneal route were administered on days 1—3, and rats were killed and brains sectioned for BrdU immunohistochemistry and cell counting on days 3, 7, 14, and Lines in upper panels of b demarcate the lateral ventricle.
Dotted line, basal level of BrdU labeling in normal, nonischemic rats. VEGF and angiogenesis in ischemic brain. This is important because of the proposed relationship between angiogenesis and neurogenesis 24 — Compared with control brains, neither ischemia nor the combination of ischemia and VEGF treatment increased vWF staining in DG Figures 6 and 7 , despite the fact that both increased BrdU labeling in this region Figure 5.
In contrast, vWF staining was increased in the penumbral region of the ischemic striatum after ischemia plus VEGF treatment, consistent with prior evidence for VEGF-induced angiogenesis in ischemic brain areas For the latter two groups, fields shown are from the ischemic hemisphere. The major finding of this study is that the administration of VEGF to rats undergoing focal cerebral ischemia reduces infarct size and enhances neurogenesis and cerebral angiogenesis.
Of particular note, these effects were observed with delayed administration of VEGF, which was given beginning at day 1 and continued until day 3 after ischemia. This regimen was adopted because a previous study showed that delayed, but not early, postischemic administration of VEGF improved neurological recovery after stroke, apparently because early VEGF treatment promoted brain edema, hemorrhagic transformation of the infarct, and spread of the ischemic lesion Neuroprotection following such delayed treatment is unusual, although it has been reported 32 , One explanation may be that most experimental neuroprotective agents have been directed against early events in ischemia, such as acute excitotoxicity, whereas VEGF may act on later events to prevent delayed cell death.
In addition, in the model we employed, ischemia may evolve more slowly than it does after more prolonged MCAO, thereby expanding the time window for cell rescue. VEGF also produced a strikingly delayed effect on neurogenesis, which was apparent only after 28 days. This suggests a mechanism of action that, while triggered within the first 3 days after ischemia, requires considerably longer to become manifest.
At least four previous studies have examined the effect of VEGF on cerebral infarct size. In contrast, van Bruggen et al. Finally, Zhang et al. These different results are not surprising considering that the studies cited differ with respect to species, whether MCAO was followed by reperfusion, whether VEGF or a VEGF-binding protein was given, the route and timing of administration, duration of follow up, and whether histological or functional criteria were used to evaluate outcome.
Our finding that intraventricular VEGF reduces infarct volume and improves neurological outcome at 3—28 days after transient focal ischemia is most consistent with the studies by Hayashi et al.
Although the mechanisms underlying VEGF-induced reduction of infarct size are uncertain, several lines of evidence, cited above, point to a direct protective effect on neurons. In the latter case, VEGF was infused by the intracerebroventricular route for 3 days, BrdU was given by the intraperitoneal route over the same period, and neurogenesis was measured 1 week later.
The observed increase in BrdU labeling of cells that coexpressed neuronal markers suggested that VEGF acted at an early proliferative phase of neurogenesis. In the present study, we found that VEGF had a delayed effect on the number of BrdU-labeled cells of neuronal lineage in the ischemic brain, consistent with increased survival of newborn neurons rather than increased proliferation.
This discrepancy can be reconciled by considering that focal cerebral ischemia itself induces neuroproliferation in SVZ and SGZ Thus, the neuroproliferative effect of VEGF that we observed in the nonischemic brain 27 may be masked by the effect of ischemia itself in the ischemic brain.
This difference implies that VEGF not only stimulates the proliferation of neuronal precursors in the nonischemic brain, but also promotes the survival of proliferating cells of neuronal lineage in the ischemic brain, consistent with the neurotrophic effects of VEGF demonstrated previously in other systems 15 — Previous studies on the role of trophic factors in neurogenesis provide clues as to how this might occur 35 , Thus, the VEGF-induced increase in survival of neuronal precursor cells could be due to either long latency, downstream effects of VEGF signaling in the same cells that are stimulated to proliferate by ischemia including priming these cells for the subsequent effects of other growth factors , or by enhanced proliferation of a separate, VEGF-responsive subpopulation characterized by more robust survival capacity.
The timing and distribution of VEGF expression correlate with angiogenesis in the normal and hypoxic developing adult rat brain 4 and the ischemic adult 9 rat brain. For example, VEGF protein expression in the ischemic penumbra increased progressively between 2 and 14 days after MCAO, and evidence of new vessel formation was present during days 7—28 9.
Intracerebral infusion of VEGF stimulates angiogenesis detectable by laminin immunostaining in rat cerebral cortex 3—7 days later 10 , In the ischemic rat brain, intravenously administered VEGF also triggers angiogenesis, as manifested by an increase in the number and volume of FITC-dextran—perfused cerebral cortical microvessels 7 days later
Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis
The neuroprotective roles for amyloid precursor protein (APR) and its soluble secreted fragment (sAPPa), a normal a-secretase cleavage product, have been. Valproic acid-mediated neuroprotection and neurogenesis after spinal cord injury : from mechanism to clinical potential. Tianci Chu;,; Hengxing Zhou;,; Lu Lu. 5-HT4 Receptor-Mediated Neuroprotection and Neurogenesis in the Enteric Nervous System of Adult Mice. Min-Tsai Liu, Yung-Hui Kuan.