Acute alterations of endothelin-1 and iNOS expression and control of the brain microcirculation after head trauma

The biosynthetic equilibrium between endothelin-1 (ET-1, a vasoconstricting agent) and nitric oxide (NO, a gas with vasodilating effects) is thought to play a role in the autoregulation of microvessel contractility and maintenance of adequate perfusion after traumatic brain injury. ET-1 is a constitutively expressed peptide, while the gene that encodes for the inducible nitric oxide synthase (iNOS, an enzyme responsible for the synthesis of excessive and toxic amounts of NO) is solely activated after brain injury. We employed the Marmarou acceleration impact model of brain injury (400 g from 2 m) to study the effect of closed head trauma on the rat brain microcirculation. Following head trauma we analyzed changes of cerebral cortex perfusion using laser Doppler flowmetry and ultrastructural alterations of endothelial cells. We temporally correlated these changes with the expression of ET-1 (immunocytochemistry) and iNOS (in situ hybridization) to assess the role of these vasoactive agents in vascular contractility and cortical perfusion. Cortical perfusion was reduced by approximately 50% during the second hour as compared to values during preceding time points after TBI, reached a peak minutes before 3 h, and subsequently showed a trend towards normalization. A significant reduction in the lumen of microvessels and severe distortion of their shape were observed after the fourth hour post-trauma. At the same time period ET-1 expression in endothelial cells was stronger than in microvessels of control animals. ET-1 expression was further increased at 24 h after TBI. iNOS mRNA synthesis was strongly upregulated in the same cells at 4 h but was undetectable at 24 h post trauma. Our combined functional, cellular and molecular approach supports the notion that ET-1 and iNOS are expressed differentially in time within individual endothelial cells of cortical microvessels for the control of cortical blood flow following closed head trauma. This differential expression further indicates a reciprocal interaction in the synthesis of these two molecules which may underlie the control of microvascular autoregulation.     

Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations

Because of the potential relationship between vascular disturbances and secondary tissue damage, we identified areas of brain which exhibited hemorrhage and leakage of protein during the acute stage after experimental brain injury and subsequently studied the development of pathologic changes, including cavity formation, neuronal necrosis, and gliosis within these regions. The development of pathologic changes was evaluated at 1, 6, and 24 h and 1, 2, and 4 weeks after lateral, fluid percussion (FP) brain injury of moderate severity in the rat. Vascular disruption in the acute stages, as evidenced by hemorrhage and leakage of Evans blue albumin, was most prominent 6 h postinjury and was maximal in the parieto-occipital cortex. From 1 to 24 h after injury, regions of the injured hemisphere, including the cortex and hippocampus, exhibited abnormal neurons which stained with acid fuchsin and Alizarin red, histochemical markers for injured neurons and calcium, respectively. These same regions suffered significant neuronal cell loss from 1 to 4 weeks after injury. The distribution of reactive astrocytes was also evaluated by immunocytochemical localization of glial fibrillary acidic protein (GFAP). By 2 weeks postinjury, a prominent cavity was present in the frontopariental and occipital cortices. Although astrogliosis was most pronounced in the cortex surrounding the cavity, prominent reactive astrocytes were widely distributed throughout the injured hemisphere. This study characterized the pathological changes which occur after experimental traumatic brain injury. In particular, we propose that neuronal cell injury in the hippocampus serves as a useful ‘window’ to assess beneficial efficacy of pharmacological intervention in the treatment of brain injury.     

体外血脑屏障模型的建立及功能测定

目的利用大鼠原代微血管内皮细胞及星形胶质细胞建立体外血脑屏障模型,并通过跨内皮细胞电阻(Trans-epithelium electrical resistant,TEER)方法对血脑屏障模型进行功能测定。方法原代分离纯化SD大鼠脑微血管内皮细胞和星形胶质细胞,用免疫荧光检测内皮细胞标志物VWF,紧密连接蛋白ZO-1,星形胶质细胞标志物GFAP;用微血管内皮细胞和星形胶质细胞在Transwell小室上建立体外血脑屏障模型,观察TEER值的动态变化。结果原代的微血管内皮细胞培养至融合后具有典型的梭形"铺路石"样外观,VWF鉴定细胞纯度达到95%以上,ZO-1免疫荧光鉴定证实细胞间形成紧密连接;原代培养的星形胶质细胞呈现具有多个突起的典型形态,GFAP鉴定细胞纯度达到95%以上;在第10 d,单独微血管内皮细胞血脑屏障模型的TEER值为(42±1.41)Ωcm2,内皮细胞和星形胶质细胞共培养血脑屏障模型的TEER值为(65±1.42)Ωcm2。结论建立了体外血脑屏障模型,通过TEER值测定证明共培养使模型更加完整,更加接近在体血脑屏障模型的特性。     

Trauma-induced cell swelling in cultured astrocytes

Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury that account for most early deaths after traumatic brain injury. An important component of brain edema after traumatic brain injury is astrocyte swelling (cytotoxic edema). To examine the pathophysiologic mechanisms of trauma-induced astrocyte swelling, we used an in vitro fluid percussion trauma model. Exposure of cultured rat astrocytes to 5 atm of pressure resulted in significant cell swelling at 1 to 24 hours posttrauma that was maximal at 3 hours. Because oxidative/nitrosative stress, mitochondrial permeability transition (mPT), and mitogen-activated protein kinases (MAPKs) have been implicated in astrocyte swelling in other neurologic conditions, we examined their potential roles in this model. We previously showed increased free radical generation after in vitro trauma and show here that trauma to astrocytes increased the production of nitric oxide. Trauma also induced mPT and increased phosphorylation (activation) of MAPKs (extracellular signal-regulated kinase 1/2, c-Jun-N-terminal kinase, and p38-MAPK); these changes were diminished by antioxidants and the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. Antioxidants, N-nitro-l-arginine methyl ester, the mPT inhibitor cyclosporin A, and inhibitors of MAPKs all significantly diminished trauma-induced astrocyte swelling. These findings demonstrate that direct mechanical injury to cultured astrocytes brings about cell swelling, and that blockade of oxidative/nitrosative stress, mPT, and MAPKs significantly reduce such swelling.     

The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes

Human and monkey brain sections were examined by immunohistochemical light and electron microscopy to determine the distribution of GLUT1, a glucose transporter isoform associated with erythrocytes and endothelial cells of the human blood-brain barrier. Protein immunoblotting of fractionated human brain membranes was performed to determine the distribution of molecular forms of the transporter. GLUT1 staining was abundant in erythrocytes and cerebral endothelium of gray and white matter but was also present diffusely in gray matter neuropil when viewed by light microscopy. Immunoelectron microscopy confirmed the gray matter and vascular localization of GLUT1, with specific GLUT1 staining seen in erythrocytes, gray and white matter endothelial cells, astrocyte foot processes surrounding gray matter blood vessels, and in astrocyte processes adjacent to synaptic contacts. No astrocytic staining was identified in white matter. Astrocyte GLUT1 staining was identified only in mature gray matter regions; undifferentiated regions of preterm (22–23 weeks gestation) cortex had GLUT1 staining only in blood vessels and erythrocytes, as did germinal matrix. Immunoblots of adult human frontal cortex revealed that two forms of GLUT1 (45 and 52 kDa) were present in unfractionated brain homogenates. Immunoblots of vessel-depleted frontal lobe revealed only the 45 kDa form in gray matter fractions, and depleted in membranes prepared from white matter regions. We conclude that the GLUT1 isoform of glucose transporter is present both in endothelium of the blood-brain barrier and in astrocytes surrounding gray matter blood vessels and synapses. Furthermore, the form present in astrocytes is likely to have a lower molecular weight than the form found in cerebral endothelium. The GLUT1 transporter may play an important role not only in astrocyte metabolism, but also in astrocyte-associated pathways supporting neuronal energy metabolism. © 1995 Wiley-Liss, Inc.     

Behavioral and morphological consequences of primary astrocytes transplanted into the rat cortex immediately after nucleus basalis ibotenic lesion

Adult male rats received transplants of dissociated 30-day old cultured cortical astrocytes into the ipsilateral frontal and parietal cortex immediately after unilateral ibotenic acid lesion of the NBM or after sham injury. We hypothesized that transplants of astrocytes into the acetylcholine-deprived cortex might provide trophic support to terminals arising from damaged NBM neurons. Twenty four hours after transplantation and every other day for 11 days post surgery, the animals were tested for locomotion and habituation in an open field. NBM lesion reduced vertical movements only as compared to no lesion and no transplant counterparts. Nine days after surgery rats with NBM lesion and astrocyte-transplants into the cortex were as impaired in the acquisition of a passive avoidance (PA) task as untreated counterparts. Animals with no lesions and transplants into the cortex also had significant PA acquisition deficits. All rats with ibotenic lesion were significantly impaired on PA retention as compared to rats with no lesions. Astrocyte-transplants survived up to 2 months after cortical implantation but these transplants produced severe laminar disruption and gliosis. This effect was greater in rats with NBM lesion than in intact animals with transplants into the cortex. These data show that astrocyte-transplants do not promote functional recovery after NBM lesion and suggest an immune rejection of the astrocyte transplants by the host brain.     

cAMP-induced stellation in primary astrocyte cultures with regional heterogeneity

It is well known that increased cAMP levels in cultured astrocytes can convert flat polygonal shaped astrocytes into process-bearing, stellate astrocytes. In this study, we have examined the possible existence of astrocyte regional heterogeneity in morphological changes in response to cAMP stimulation. Primary astrocyte cultures were prepared from six different regions of neonatal rat brains, including cerebral cortex, hippocampus, brain stem, mid brain, cerebellum, and hypothalamus. After about 2 weeks in culture, the astrocyte culture medium was changed to DMEM containing various concentrations of 8-CPT-cAMP, a membrane permeable cAMP analog, for 2 h. We found that 250 microM 8-CPT-cAMP produced a maximum effect causing >95% stellation in all regional astrocytes except hypothalamic astrocytes (56% stellation). At lower cAMP concentrations, cell stellation most effectively occurred in cerebellar astrocytes. To examine further the regional heterogeneity of astrocyte morphological changes, glutamate was added together with 8-CPT-cAMP to block cAMP-induced astrocyte stellation. Interestingly, glutamate blockage on cAMP-induced astrocyte stellation was brain region-specific in that cerebral and hippocampal astrocytes were effectively blocked by glutamate when compared to other regional astrocytes. Furthermore, glutamate inhibited isoproterenol-induced astrocyte stellation in a region-specific manner similarly as in cAMP-induced stellation. The present study demonstrates that astrocytes derived from different regions of the neonatal rat brain maintain different levels of morphological plasticity in culture.     

Advances in the vascular pathophysiology of ischemic stroke

The cerebral vascular supply is constructed to protect the cerebral hemispheres and brainstem from the consequences of blood flow cessation. Reversal of blood flow around local obstructions is a feature of the microvascular beds of the striatum and cerebral cortex. Cerebral capillaries of these beds consist of endothelial cells, basal lamina, and astrocyte end-feet that sit in close apposition. The interaction of astrocytes with neurons indicates the close relationship of microvessels to neurons. These relationships are altered when blood flow ceases in the supplying artery. Increased endothelial cell permeability and endocytoses lead to edema formation, and matrix degradation is associated with hemorrhage. Autoregulation is lost. Ischemia initiates leukocyte adhesion receptor expression, which is promoted by cytokine generation from the neuropil and activated monocytes. "Preactivation" may further augment the inflammatory responses to ischemia. The activation of cerebral microvessels by ischemia is heterogeneous, involving alterations in integrin-matrix interactions, leukocyte-endothelial cell adhesion, permeability changes, and the "no-reflow" phenomenon due to platelet activation, fibrin formation, and leukocyte adhesion. Ischemia produces swelling of the microvascular endothelium, and rapid detachment and swelling of the astrocyte end-feet. Ischemic injury targets the microvasculature, where the inflammatory responses are initiated and contribute to tissue injury.     

Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase-Overexpressing Mouse

Transgenic mice overexpressing spermine oxidase (SMO) in the cerebral cortex (Dach-SMO mice) showed increased vulnerability to excitotoxic brain injury and kainate-induced epileptic seizures. To investigate the mechanisms by which SMO overexpression leads to increased susceptibility to kainate excitotoxicity and seizure, in the cerebral cortex of Dach-SMO and control mice we assessed markers for astrocyte proliferation and neuron loss, and the ability of kainate to evoke glutamate release from nerve terminals and astrocyte processes. Moreover, we assessed a possible role of astrocytes in an in vitro model of epileptic-like activity in combined cortico-hippocampal slices recorded with a multi-electrode array device. In parallel, as the brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms, we analyzed the oxidative status of the cerebral cortex of both SMO-overexpressing and control mice by evaluating enzymatic and non-enzymatic scavengers such as metallothioneins. The main findings in the cerebral cortex of Dach-SMO mice as compared to controls are the following: astrocyte activation and neuron loss; increased oxidative stress and activation of defense mechanisms involving both neurons and astrocytes; increased susceptibility to kainate-evoked cortical epileptogenic activity, dependent on astrocyte function; appearance of a glutamate-releasing response to kainate from astrocyte processes due to activation of Ca²⁺-permeable AMPA receptors in Dach-SMO mice. We conclude that reactive astrocytosis and activation of glutamate release from astrocyte processes might contribute, together with increased reactive oxygen species production, to the vulnerability to kainate excitotoxicity in Dach-SMO mice. This mouse model with a deregulated polyamine metabolism would shed light on roles for astrocytes in increasing vulnerability to excitotoxic neuron injury.     

Free amino acids in the synaptosome and synaptic vesicle fractions of different bovine brain areas

Free amino acids were quantitatively estimated in intact tissues and isolated synaptosome and synaptic vesicle fractions of the bovine brain regions with the aid of a sensitive amino acid analyzer. The brain areas studied were frontal, parietal and occipital cerebral cortices, cerebellar cortex, caudate and lenticular nuclei, superior colliculi, thalamus, pons and medulla. The most abundant amino acid in tissue samples and synaptosome fractions was glutamic acid, followed by glutamine, aspartic acid, GABA and taurine. The dominatating amino acid in all isolated synaptic vesicle fractions was taurine. The concentrations of glutamic acid, glutamine, GABA and aspartic acid were generally much lower. The 5 transmitter candidates, viz. GABA, glycine, glutamic acid, as particaid and taurine, comprised about one-half of the total amino acids in all samples. Taurine was the only amino acid highly enriched in the vesicle fractions. This enrichment was discernible in all brain areas. It is suggested therefore that taurine is rather a ubiquitous associate of synaptic membrane structures than a specific inhibitory transmitter.     

Repetitive injury and absence of monocytes promote astrocyte self‐renewal and neurological recovery

Unlike microglia and NG2 glia, astrocytes are incapable of migrating to sites of injury in the posttraumatic cerebral cortex, instead relying on proliferation to replenish their numbers and distribution in the affected region. However, neither the spectrum of their proliferative repertoire nor their postinjury distribution has been examined in vivo. Using a combination of different thymidine analogs and clonal analysis in a model of repetitive traumatic brain injury, we show for the first time that astrocytes that are quiescent following an initial injury can be coerced to proliferate after a repeated insult in the cerebral cortex grey matter. Interestingly, this process is promoted by invasion of monocytes to the injury site, as their genetic ablation (using CCR2^?/? mice) increased the number of repetitively dividing astrocytes at the expense of newly proliferating astrocytes in repeatedly injured parenchyma. These differences profoundly affected both the distribution of astrocytes and recovery period for posttraumatic behavior deficits suggesting key roles of astrocyte self‐renewal in brain repair after injury.     

Capillary regeneration following thermal lesions in the mouse cerebral cortex

Summary Cold lesions were induced in the parietal cortex of 20 mice and capillary revascularisation of the necrotic zone in the subsequent four weeks was observed by light and electron microscopy. During the second week after injury, capillaries grew into the lesion from the thickened pia. Each vessel was covered by several thin lamellae of pial cell and was accompanied by bands of collagen.Capillaries which grew into the necrotic zone from the surrounding brain during the 2nd–3rd weeks after injury were all surrounded by astrocyte processes; there was also a pericapillary space which contained pericyte processes and a few collagen fibres. Lacunae lined by basement membrane and surrounded by processes of one or more astrocytes were observed during the early stages of revascularisation. Each lacuna contained a few collagen fibrils together with cell processes which were similar to the pericyte processes around regenerated capillaries. Cells resembling immature endothelial cells were occasionally seen within the lacunae.The hypotheses proposed here are, that the regenerating capillaries grow through or along the astrocyte lacunae and that the course of capillary regeneration is in this way influenced and guided by the astrocytes.     

Expression and activation of EphA4 in the human brain after traumatic injury

Glial scars that consist predominantly of reactive astrocytes create a major barrier to neuronal regeneration after traumatic brain injury (TBI). In experimental TBI, Eph receptors and their ephrin ligands are upregulated on reactive astrocytes at injury sites and inhibit axonal regeneration, but very little is known about Eph receptors in the human brain after TBI. A better understanding of the functions of glial cells and their interactions with inflammatory cells and injured axons will allow the development of treatment strategies that may promote regeneration. We analyzed EphA4 expression and activation in postmortem brain tissue from 19 patients who died after acute closed head injury and had evidence of diffuse axonal injury and 8 controls. We also examined downstream pathways that are mediated by EphA4 in human astrocyte cell cultures. Our results indicate that, after TBI in humans, EphA4 expression is upregulated and is associated with reactive astrocytes. The expression was increased shortly after the injury and remained activated for several days. EphA4 activation induced under inflammatory conditions in vitro was inhibited using unclustered EphA4 ligand. These results suggest that blocking EphA4 activation may represent a therapeutic approach for TBI and other types of brain injuries in humans.     

Evaluation of brain perfusion SPECT using an easy Z-score imaging system (eZIS) as an adjunct to early-diagnosis of neurodegenerative diseases

The eZIS allows computer-assisted statistical analysis of brain perfusion SPECT images. We evaluated the diagnostic value of brain perfusion SPECT using eZIS in patients with various neurodegenerative diseases at a very early stage, within one year from onset.

Methods

SPECT using eZIS was performed for patients with Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD,), idiopathic Parkinson disease (PD) and vascular Parkinsonism (VP), multiple systemic atrophy of the cerebellar type (MSA-C), cortical cerebellar atrophy (CCA) and amyotrophic lateral sclerosis (ALS).

Results

Decreased rCBF was observed in the posterior cingulate cortex, precuneus and parietal cortex in AD; in the frontal gyrus and insula in FTD; in the occipital lobe, precuneus gyrus and posterior cingulate cortex in DLB; in the striatum and the thalamus in VP; in the cerebellum in CCA; in the cerebellum and pons in MSA-C and in the frontal cortex including the central sulcus in ALS. Increased rCBF in the striatum, thalamus and cerebellar dentate nuclei were observed in PD.

Conclusions

A specific rCBF pattern was observed for each disease using eZIS analysis, consistent with previous reports. Our results showed eZIS can be easily used as an adjunct to early-diagnosis of neurodegenerative diseases in any hospital.     

Brain gamma-aminobutyric acid deficiency in dialysis encephalopathy

We measured levels of gamma-aminobutyric acid (GABA) in the CSF and in the autopsied brain of patients with dialysis encephalopathy. GABA concentrations were low in the CSF of three of five living patients. Mean GABA content was reduced by 30 to 50% in five brain regions (frontal, occipital, and cerebellar cortex, caudate nucleus, and medial dorsal thalamus) in five fatal cases. GABA content was normal in brain regions where GABA is characteristically reduced in Huntington's disease. Choline acetyltransferase activity was diminished (by 25 to 35%) in cerebral cortex of the dialysis encephalopathy patients.     

高血压鼠局部脑梗塞后脑超微结构改变动态观察

本文选用肾血管性高血压鼠(RHR)复制大脑中动脉闭塞(MCAO)模型,其后2h至7d分8次取不同区域脑组织进行透射电镜动态观察超微结构的改变。显示局部脑梗塞后发生全脑性改变,其损害程度和出现时间梗塞区最早,以坏死为主,呈完全不可逆性损害;边缘区稍后,主要是微血管塌陷和微血栓形成及部分脑细胞坏死,呈部分可逆性损害,远隔区和镜区最迟,以内皮和星形细胞水肿为主,呈可逆性损害,认为用RHR复制MCAO,更接近于高血压性脑血管损害基础上发生脑梗塞的临床病理改变,全脑超微结构的动态性改变中微血管损害起着重要作用。     

The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent.

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen-glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on alphabeta-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by alpha-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin alpha6beta4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.     

急性局灶性脑挫裂伤后大鼠血脑屏障改变的实验研究

目的:研究急性局灶性脑挫裂伤后大鼠血脑屏障的改变及对脑水肿的影响。方法:采用Feeney's自由落体撞击法建立急性局灶性脑挫裂伤模型。每组6只测量伤侧脑组织伊文思蓝(Evans Blue,EB)含量、脑组织含水量。每组3只电镜观察微血管内皮细胞超微结构改变。结果:急性局灶性脑挫裂伤后24h脑组织含水量为(79.79±0.83)%,与正常对照组(78.68±0.63)%相比有明显差异(P<0.01),脑损伤后6h脑组织中EB含量为(362.12±28.16)ug/g,与正常对照组(11.89±2.28)ug/g相比有明显差异(P<0.01);脑损伤后30min,微血管内皮细胞有轻度受损迹象,伤后3h毛细血管腔内有微绒毛形成,伤后6h微绒毛增多,伤后24~72h毛细血管腔明显狭窄。结论:脑含水量的变化与脑组织中EB含量变化不同步,BBB的开放先于脑水肿的形成。BBB的开放与微血管的机械性损伤、内皮细胞吞饮小泡增加、内皮细胞紧密连接中断有关,也与早期缺血、缺氧关系密切。     

弥漫性脑损伤微血管形态学研究

目的 运用形态计量学方法研究弥漫性脑损伤（DBI）大鼠模型的微循环及胶质细胞形态学改变，并观察萘呋胺酯（NF）对DBI的治疗作用。方法 采用Marmarou的DBI模型，光镜下测量顶叶皮质内微血管及其周围水肿区的截面面积，电镜下半定量测定皮质区毛细血管周的水肿范围及胶质细胞胞体的肿胀程度。结果 外伤后2、6、24小时平均微血管截面面积与对照组比较无显著缩小，6、24小时微血管周水肿明显增加。NF组伤后2小时微血管无扩张，但其周围水肿增加，24小时两者均改善。电镜下2、24小时毛细血管周水肿明显；胶质细胞胞体肿胀在2小时明显，24小时无显著差异；NF在2小时能减轻胶质细胞肿胀程度，但对毛细血管周水肿范围影响不大。结论 形态计量学方法能准确反映脑外伤后微循环及脑水肿改变。外伤早期慎用血管扩张药物。     

Neuroprotective agents in brain injury: a partial failure?

Brain injury leads to inflammation, stress, and cell death. Neurons are more susceptible to injury than astrocytes, as they have limited antioxidant capacity, and rely heavily on their metabolic coupling with astrocytes to combat oxidative stress. Both normally and after brain injury, astrocytes support neurons by providing antioxidant protection, substrates for neuronal metabolism, and glutamate clearance. Although astrocytes are generally more resilient than neurons after injury, severe damage also results in astrocyte dysfunction, leading to increased neuronal death. This mini review provides a very insightful and brief overview on a few examples of promising neuroprotective compounds targeting astrocyte function, with specific attention on how these treatments alter astrocyte response or viability, and how this may be critical for neuronal survival following brain injury.