Research reportReduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice subjected to permanent focal ischemia
Introduction
`Neuropoietic' factors influence the survival, differentiation and connectivity of various neuronal populations. They belong to the neurotrophin, fibroblast growth factor (FGF), transforming growth factor (TGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), and interleukin families (for a review, see e.g., Ref. [30]). Such factors, which are dynamically regulated in response to epileptic, hypoglycemic, ischemic and traumatic injuries, actively participate in the control of neuronal cell death (reviewed in Refs. 13, 21). In rodent models of focal cerebral ischemia based on middle cerebral artery occlusion (MCAO), ischemic brain damage results in neuronal loss within vulnerable regions of the striatum and cortex. Several mRNAs species exhibit enhanced levels following MCAO, including mRNAs of neuroprotective agents, such as nerve growth factor (NGF, [20]), brain-derived neurotrophic factor (BDNF, [2]), acidic and basic FGFs 11, 33, TGF-β1 [36], and neurotoxic agents, such as interleukin-1 (IL-1, [40]) and tumor necrosis factor-α (TNF-α, [24]).
The in vivo neuroprotective potential of NGF after either intracerebroventricular NGF injection 3, 4, 31or implantation of NGF-producing fibroblasts [28]has been demonstrated on hippocampal neurons, in different paradigms of experimental ischemia. However, in vitro, NGF can protect cultured hippocampal as well as cortical neurons against hypoglycemic damage, glutamate-induced neurotoxicity or iron-induced degeneration 5, 32, 41. To ascertain an in vivo neuroprotective effect of NGF on cortical neurons, we have used a model of pure cortical infarction following MCAO in mice [9]. The electrocoagulation of the left MCA in the mouse provokes a moderate and progressive infarct localized in the temporal and parietal cortices. Twenty four hours after the MCAO, the infarct is consolidated and about 20% of the brain volume is destroyed [9]. The availability of transgenic (tg) mice expressing the NGF gene after induction, has provided us with the opportunity to test the neuroprotective effect of NGF after permanent focal ischemia. MCAO was performed on a mouse strain transgenic for NGF in which encoding sequences are controlled by a part of the inducible promoter of the proto-oncogene c-fos [27]. Transcription of transgenic sequences and NGF protein synthesis can be notably increased after the stimulation of the promoter both in vitro and in vivo 27, 29. Considering that the c-fos gene is among the first set of genes activated in cortical structures by ischemic insults [15], we speculated that NGF synthesis could be rapidly and locally induced in tg mice after MCAO, thus, providing a useful tool to investigate the role of NGF in ischemia-related brain damage in vivo. We report here a major effect of NGF on the survival of cortical neurons following MCAO in mice resulting in an important reduction of brain infarction, mainly through modulation of the apoptotic cell death pathway.
Section snippets
Surgical procedure and measurement of the infarct volume
All the studies with mice have been conducted with respect to the EC legislation on animal care. Male tg mice homozygous for the transgene or wt mice of the same genetic background (C57Bl/6×DBA/2)F1 weighing 20–25 g were anesthetized intraperitoneally with chloral hydrate (500 mg/kg). Coagulation of the left middle cerebral artery was performed as described [9]. After surgery, animals were placed in a warm environment until they recovered from anesthesia. Three, 24 h and 7 days after MCAO, mice
Measurement of infarct volumes in wt and tg mice
Volumes of infarcted brain were measured in wt and tg groups, 3, 24 h and 7 days after MCAO (Fig. 1). Three hours post-occlusion, all mice showed cortical infarction and the measured volumes were equivalent between the two groups. On the contrary, 24 h after MCAO, the volume of the infarct had significantly increased in wt mice when compared to the volume measured at 3 h (t-test, p<0.05) whereas it was comparable to the 3 h-volume in tg mice. The comparison of infarct volumes between wt and tg
Discussion
The current study shows that tg mice subjected to unilateral MCAO exhibit a permanent 40% reduction of cortical infarction when compared to their wt counterpart. The neuroprotective effect of NGF has been unambiguously reported in animal models of epilepsy and degeneration induced by the administration of excitotoxic agents 8, 34. However, results obtained in models of transient ischemia are still controversial 3, 4, 28, 31and, to our knowledge, have never been reported for permanent ischemia
Acknowledgements
C.G. is a fellow of Ministère de l'Education Nationale, de la Recherche et de la Technologie. M.M.-B. is a fellow of France Parkinson. We thank Brigitte Hamon and Juliette Martin for critically reading the manuscript.
References (41)
- et al.
Induction of brain-derived neurotrophic factor (BDNF) and the receptor trkB mRNA following middle cerebral artery occlusion in rat
Neurosci. Lett.
(1996) - et al.
Chronic infusion of nerve growth factor does not rescue pyramidal cells after transient forebrain ischemia in the rat
Neurosci. Lett.
(1992) - et al.
NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis
Neuron
(1991) - et al.
Decreased choline acetyltransferase activity in nerve growth factor-transgenic mice during brain development
Neuroscience
(1994) - et al.
Acidic fibroblast growth factor-like immunoreactivity in the rat brain following cerebral infarction
Brain Res.
(1994) - et al.
Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 messenger RNA and protein and p53-inducible genes Bax and Gadd-45 in brain areas showing DNA fragmentation
Neuroscience
(1996) Trophic factor response to neuronal stimuli or injury
Curr. Opin. Neurobiol.
(1995)- et al.
Temporal profile of nerve growth factor-like immunoreactivity after transient focal cerebral ischemia in rats
Brain Res.
(1996) - et al.
In situ detection of DNA fragmentation after focal cerebral ischemia in mice
Mol. Brain Res.
(1995) - et al.
Neurotrophins and brain insults
Trends Neurosci.
(1994)
Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion
Mol. Brain Res.
Cell-type specific expression and regulation of a c-fos-NGF fusion gene in neurons and astrocytes of transgenic mice
Mol. Brain Res.
Cytokines and the nervous system: II. Action and mechanisms of action
Trends Neurosci.
Protective effect of nerve growth factor against glutamate-induced neurotoxicity in cultured cortical neurons
Brain Res.
Increased expression of basic fibroblast growth factor (bFGF) following focal cerebral infarction in the rat
Mol. Brain Res.
Increased levels of nerve growth factor (NGF) protein and mRNA and reactive gliosis following kainic acid injection into the rat striatum
Neurosci. Lett.
Endonuclease activation following focal ischemic injury in the rat brain
Brain Res.
Transforming growth factor-β1 exhibits delayed gene expression following focal cerebral ischemia
Brain. Res. Bull.
In situ hybridization analysis of c-fos and c-jun expression in the rat brain following transient forebrain ischemia
Brain Res.
Expression of c-fos and c-jun family genes after focal cerebral ischemia
Ann. Neurol.
Cited by (41)
Voltage-dependent potassium channel Kv4.2 alleviates the ischemic stroke impairments through activating neurogenesis
2021, Neurochemistry InternationalCitation Excerpt :Neurotrophins are important regulators of neuronal survival, development, function, and plasticity (Huang and Reichardt, 2001). Further experiments demonstrate that the administration of NGF can reduce apoptotic cell death and infarct volume (Cao et al., 2018; Guegan et al., 1998; Holtzman et al., 1996), ameliorate delayed neuronal death (Shigeno et al., 1991), steer microglia into neuroprotective phenotype (Rizzi et al., 2018), boost angiogenesis (Zhu et al., 2011), and promote neural regeneration and functional recovery (Zhu et al., 2011). BDNF is an alternative neurotrophin which also plays an important role in neuronal differentiation and learning memory after stroke (Soler-Llavina et al., 2003; Zhao et al., 2015).
Therapeutic Effects of Simultaneous Delivery of Nerve Growth Factor mRNA and Protein via Exosomes on Cerebral Ischemia
2020, Molecular Therapy Nucleic AcidsCitation Excerpt :NGF also has a broad spectrum of protective effects on various neurons, glial cells, and vascular endothelial cells under different pathological circumstances.3,4 Further experiments demonstrate that the administration of NGF can reduce apoptotic cell death and infarct volume,5–8 ameliorate delayed neuronal death,9 steer microglia into neuroprotective phenotype,10 boost angiogenesis,11 and promote neural regeneration and functional recovery.12 In the context of acute cerebral ischemia, the endogenous expression of NGF decreased significantly in infarcted cortex, highlighting the importance to deliver exogenous NGF.13
Amitriptyline is a TrkA and TrkB Receptor Agonist that Promotes TrkA/TrkB Heterodimerization and Has Potent Neurotrophic Activity
2009, Chemistry and BiologyCitation Excerpt :NGF, gambogic amide, or amitriptyline pretreatment significantly protected hippocampal neurons from apoptosis, while other tricyclic drugs tested had no effect (Figure 1D and data not shown). NGF reduces cortical infarction and apoptosis in transgenic mice and protects PC12 cells from apoptosis in oxygen-glucose deprivation (OGD) (Beck et al., 1992; Guegan et al., 1998). To explore whether amitriptyline and/or other tricyclics could protect hippocampal neurons from OGD-provoked apoptosis, we pretreated primary cultures with various tricyclic drugs, followed by OGD stimulation for 3 hr.
PTD-XIAP protects against cerebral ischemia by anti-apoptotic and transcriptional regulatory mechanisms
2006, Neurobiology of DiseaseNeuroprotection by drug-induced growth factors
2003, International Congress Series
- 1
Present address: UPRES-EA 2128, Faculté de Médecine, CHU Côte de Nacre, 14033 Caen Cedex, France.