1、Molecular Neurobiology/10.1007/s12035-018-1203-9Growth Factors and Neuroglobin in Astrocyte Protection Against Neurodegeneration and Oxidative StressRicardo Cabezas1,2 & Eliana Baez-Jurado 1 & Oscar Hidalgo-Lanussa1 & Valentina Echeverria 3,4 & Ghulam Md Ashrad5 &Amirhossein Sahebkar6,

2、7,8 & George E. Barreto1,9Received: 10 April 2018 / Accepted: 26 June 2018# Springer Science+Business Media, LLC, part of Springer Nature 2018AbstractNeurodegenerative diseases, such as Parkinson and Alzheimer, are among the main public health issues in the world due to their effects on life quality

3、 and high mortality rates. Although neuronal death is the main cause of disruption in the central nervous system (CNS) elicited by these pathologies, other cells such as astrocytes are also affected. There is no treatment for preventing the cellular death during neurodegenerative processes, and curr

4、ent drug therapy is focused on decreasing the associated motor symptoms. For these reasons, it has been necessary to seek new therapeutical procedures, including the use of growth factors to reduce -synuclein toxicity and misfolding in order to recover neuronal cells and astrocytes. Additionally, it

5、 has been shown that some growth factors are able to reduce the overproduction of reactive oxygen species (ROS), which are associated with neuronal death through activation of antioxidative enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and neuroglobin. In the present review

6、, we discuss the use of growth factors such as PDGF-BB, VEGF, BDNF, and the antioxidative enzyme neuroglobin in the protection of astrocytes and neurons during the development of neurodegenerative diseases.Keywords PDGF-BB . Neuroglobin . Astrocyte . Oxidative stress . Neurodegeneration Introduction

7、* George E. B.co; 1Departamento de Nutricin y Bioqum ica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogot D.C., Colombia2Departamento de Ciencias Bsicas, Universidad Santo Toms, Bucaramanga, Colombia3Facultadde Cienciasde la Salud, Universi

8、dad San Sebastin, Lientur 1457, 4030000 Concepcin, Chile4Research and Development, Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA5King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia6Neurogenic Inflammation Research Center, Mashhad University of Medical Scienc

9、es, Mashhad, Iran7Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran8School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran9Instituto de Ciencias Biomdicas, Universidad Autnoma de Chile, Santiago, ChileNeurodeg

10、enerative diseasesare among themainpublichealth problems in the world. It has been estimated that by the year 2020, there will be around 40 million people affected in the world by pathologies such as Alzheimers disease (AD), Parkinsons disease (PD), epilepsy, multiple sclerosis, and ce- rebrovascula

11、r accidents. Likewise, it is expected thatby 2030, mortality fromneurodegenerative diseases willreach 12.22% of global population 1.PD manifests with a heterogeneity of symptoms such as resting tremor, bradykinesia, muscle hypertonia, postural insta- bility, and cognitive and language alterations, w

12、hich seriously affect the quality of life in patients 2, 3. These symptoms are due to the selective degeneration of dopaminergic neurons (DA) of the substantia nigra pars compacta (Fig. 1), which results in an exacerbated decrease in dopamine levels46.The current pharmacological treatments for PD su

13、ch as levodopa, carbidopa, dopamine receptor agonists, COMT (catechol-O-methyltransferase), or MAO-B (monoamine oxi- dase) inhibitors and deep brain stimulation are symptomatic and mainly focus on maintaining or prolonging the dailyFig. 1 Mitochondrial effects in PD. Alterations in mitochondrialprot

14、eins (parkin (PARK2) or PINK1) due to mutations or environmental effects may induce mitochondrial damage and increase ROS, along with drop inmembranepotentialmitochondrial(m), formationof-synuclein ag- gregates, and activation of apoptotic mechanisms in DAs are considered as hallmarks during PD onse

15、tactivities of patients, without interfering with the progression of the disease 79. Likewise, these pharmacological treat- mentslead to motorcomplications in 5090% ofcasestogeth- er with a loss in their effectiveness after 2 to 5 years 8. For this reason, it has been necessary to seek new treatment

16、s and methodologies for this pathology including the use of simva- statin and other non-steroidal agents, overexpression of chap- erone proteins such as GRP78 to reduce misfolding and - synucleintoxicity, transplantationofmesenchymalstemcells, spinal cord electric stimulation, and the use of growth

17、factors 1013.Different growth factors such as fibroblast growth factor (FGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and platelet-derived growth factor (PDGF) have been used in variousmodelsofneuroprotectionincludingcelllines,

18、animal models, and clinical trials. It has been observed that these growth factors protect neurons and glial cells against excitotoxic and oxidative insults through the production of antioxidant enzymes, chaperones, activation of cellular sur- vival pathways, and mitochondrial protection 1318. Unfor

19、tunately, growth factors such as BDNF and NGF, when used in human clinical trials, showed harmful side effects including nausea and extreme pain 19.In the case of PDGF, it has been shown that some isoforms have neuroprotective effects against ischemic damage in rat pyramidal neurons, N-methyl-D-aspa

20、rtate (NMDA) insult in retina of murine models, 6-OHDA in neurons, and TATtoxin of HIV 18, 2022. Similarly, recent clinical trials have re- ported that intracerebroventricular infusion of different doses ofplatelet-derivedgrowthfactor,isotype BB(PDGF-BB) pro- duced no adverseeffects in patients13. T

21、heseresultssuggest that PDGF-BB has promising protective effects in the treat- ment of neurodegenerative diseases including PD.Althoughdopaminergicneuronsarethemaincellsaffected in PD, numerous studies have demonstrated the participation of glial cells (microglia, astrocytes, and oligodendroglia) in

22、 the development of inflammatory events and degenerative processes that are present in PD 2326. These include aug- mented astrocytic reactivity in post-mortem brains of patients with PD, increased release of interferon- and neurotrophic factors, high levels of glutathione peroxidase (GPx), and in- c

23、reases in the endocytosis of -synuclein by astrocytes 27. Taking into account the abovementioned findings, this review highlights the need for novel neuronal and astrocytic protec- tion strategies. We also sought to provide evidence on the efficacy of new protective molecules such as neuroglobin (ng

24、b1), PDGF-BB, and other growth factors and to introduceMol Neurobiolnovel therapeutic strategies aimed at reducing mitochondrial oxidative damage in PD.Mitochondria and NeurodegenerationMitochondria are critical organelles for cell survival and nor- mal development, since these organelles are the ma

25、in modu- lators of cellular energy through the electron transport chain and ATP synthesis. They are also the main regulators of apo- ptotic death and aging and are involved in the control of cal- cium homeostasis and ROS production 2831. Variousneu- rodegenerative diseases, such as AD, stroke, Hunti

26、ngtons disease (HD), and PD, are associated with mitochondrial dis- function, increased ROSproduction, andactivation of apopto- sis 31.Currently, it is thought that the development of PD is either genetic or idiopathic. For example, several genes involved in its etiopathogenesis have been identified

27、, and these include PARK8, PARK2, PARK7 (DJ-1), PINK1, and SNCA, whichencode for parkin and -synuclein that accumulate in Lewy plaques or bodies in dopaminergic neurons 1, 5. Some of these proteins, LRRK2, PINK1, and PARK7, are also in- volved in the regulation of mitochondrial functions (Fig. 1) li

28、ke the maintenance of mitochondrial membrane potential (m) and the production of reactive oxygen species (ROS) and are thus affected during PD development 32, 33. Likewise, it has been suggested that the response to un- folded proteins (UPR) is also involved in the development of PD 3436. In this ca

29、se, increased ROS (reactive oxygen species) levels and imbalance in calcium levels that occur during the PD onset lead to an increase in the accumulation of misfolded proteins, including -synuclein, which in turn induces the activation of regulatory proteins of the UPR such as PERK kinase, inositol

30、1-dependent enzyme (Ire1), tran- scription factor 6 (ATF6), and the chaperone GRP78/Bip 3437.Various studies have shown that the production and accu- mulation of cytotoxicfactorsproducedegenerativealterations in neurons 3841. Neurotoxicity has been attributed to high levels of ROS, nitric oxide, int

31、erleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-), which can affect mitochondrial energetic processes in dopaminergic neurons and as consequence the activation of apoptotic pathways (Fig. 1) through a mechanism dependent on cytochrome c and caspase 3 40. Similarly, envi

32、ronmental and occupational factors have been shown to explain the rise in PD prevalence. Some of which include exposure to pesti- cides and herbicides (including rotenone and paraquat) by agricultural workers, and other factors include genetic envi- ronmentalinteractions, dietaryfactorssuch as consu

33、mptionof polyunsaturated fatty acid, UPR, or the composition of the intestinal microbiome 36, 39, 42. For these reasons,maintenance of mitochondrialproperties in neuronsandastro- cytes are of main importance during brain injury and neuro- degeneration (Barreto et al. 2011).Astrocytic Functions: Inte

34、ractions Between Neurons and Astrocytes in PDAstrocytes are the most common type of cells in the brain of mammals and make up the glia along with oligodendrocytes and microglial cells 43. These cells are organized in a syn- cytialnetworkandarestronglycommunicatedwitheachother and, in turn, with othe

35、r cells such as pericytes, endothelial cells, and neurons 44. Astrocytes (Fig. 2) are fundamental for processes such as the development and/or maintenance of the blood-brain barrier, promotion of neurovascular coupling, recruitmentofcellsthroughtherelease of chemokines, release of gliotransmitters,

36、regulation of calcium levels, release and transport of glutamate by calcium signaling through the glu- tamate aspartate transporter (GLAST) and excitatory amino acid transporter (EAAT), maintenance of the general metabo- lism of the brain, control of cerebral pH, uptake of GABA (- aminobutyricacid)

37、by specifictransporters, andproductionof antioxidant enzymes 4548. During brain damage (e.g., ox- idativestress), theseprocessesaretemporarilyorpermanently affected and the consequent impact on neuronal cells can lead to pathological conditions and neurodegenerative diseases 45, 46. In this regard,

38、it is important to note that neurons aremoresusceptible to injurythanastrocytessincetheyhavea lower antioxidant capacity and require a greater deal of meta- bolic couplingwithastrocytes to combatoxidative stress 45. Both under normalcircumstances and after brain injury, astro- cytes provide neurons

39、with antioxidant protection, neuro- trophic factors, substrates for neuronal metabolism, and glu- tamate reuptake 28, 49. Although astrocytes are generally more resistant than neurons during traumatic or degenerative insult, these cells can also suffer severe damage which will result in increased ne

40、uronal death 49.Astrocytes respond to most types of brain insults (infections, traumas, ischemia, oxidative stress, and neurodegenerative stim- uli) by a process called reactive astrogliosis 5052. This pro- cess involves both morphological and molecular changes (Fig.2) including increases in the exp

41、ression of glial fibrillary acid protein (GFAP), vimentin, nestin and RhoA, glutamate uptake, protection against oxidative stress through the production of glutathione, neuroprotection by the release of adenosine, degra- dation of beta-amyloid peptides, regulation of the blood-brain barrier, and for

42、mation of glial scars. It is noteworthy that in some cases, reactive astrocytes can release inflammatory cytokines including tumor necrosis factor (TNF) and ROS 45, 5357.In thecaseof PD, there is conflicting informationregarding the role of astrogliosis during disease onset. Some studies have shown

43、that an increase in number of reactive astrocytesFig. 2 Rotenone and PDGF-BB effects in experimental models of PD. Various toxins have been used as experimental models in PD including paraquat or rotenone and neurotoxins such as 6-hydroxydopamine (6- OHDA) and MPP+. Paraquat, 6-OHDA, and MPP+ use th

44、e dopamine transporter (DA) to enter the dopaminergic neurons, whereas rotenone due to its lipophilic structure does not require this transporter. These toxins can induce cellular and molecular alterations including the inhibi- tion of mitochondrial complex I, formation of aggregates of -synuclein,

45、decrease in ATP production, ROS overproduction, and release of pro-apoptotic molecules such as cytochrome c. In turn, this molecule, in the cytosol,activatescaspase9andtriggersthecanonicalapoptoticactivation in dopaminergic neurons (a). PDGF-BB decreases the damaging effects induced by rotenone at v

46、arious levels, including modulation of intracel- lular calcium uptake, attenuated ROS production, regulation of morpho- logicalchanges, mitochondrialprotection, and activationoftranscription factors such as NF-B, thus overexpressing neuroprotective molecules such as neuroglobin. Furthermore, neurogl

47、obin (ngb1) has protective ac- tions on mitochondria by controlling oxidative stress production (b)is indicative of the importance of these cells in the repair of dopaminergic neurons 58, 59, while other studies have shown that the presence of reactive astro- cytes in postmortem tissues of patients

48、with PD is quite low 60, 61, the latter suggesting that excessive accu- mulation of -synuclein could suppress the protection exerted by astrocytes. Therefore, it is necessary to carry out additional studies on astrocytic activation in the context of the development of PD, including clinical trials.

49、On the other hand, different biological or envi- ronmental toxins have been used, especially herbicides and pesticides such as rotenone, paraquat, or MPTP in PD models, since these compounds can induce astrocyte reactivity and microgliosis, as well as neuronal death, mitochondrial dysfunction, oxida

50、tive stress, and nuclear fragmentation 6267. All these processes resemble what happen during the initial stages of PD 39. The rotenone model of PD is discussed in more details in the next section.The Rotenone Model of Parkinsons DiseaseRotenone is a highly lipophilic flavonoid extracted from the roo

51、ts of the plants belonging to the genus Derris and Lonchocarpus of the Leguminosae family 68. This molecule is well known as an insecticide, and its main mode of action is through the inhibition of electron transport in the mitochon- drial complex I where it blocks the production of ATP, conse- quen

52、tlyaffectingcellularmetabolism39, 69. Theimmediate inhibition of the mitochondrial respiratory chain leads to an increase in the production of ROS such as hydrogen peroxide and superoxide radical together with the peroxidation of cell membrane and DNA damage 1, 5, 29, 69, 70. The cellular andmolecul

53、areffectscaused by rotenoneincludetheselective degenerationofthenigrostriataldopaminergicsystem, activa- tion of astrogliaandmicroglia, formationandaccumulationof an altered form of -synuclein and Tau proteins associated with dopaminergic neuron damage (Fig. 2), stress of endo- plasmic reticulum (UP

54、R), overexpression of chaperones(GRP78), alterations in axonal formation associated with de- creased activity of Cdc42 and Rac, and activation of apoptotic pathways mediated by BAD and caspases 3 and 9 1, 5, 39, 68, 7176. Likewise, it has been determined that rotenone can act independently of its in

55、hibitory effects on complex I, for example, rotenone affects the stability of microtubules, inhibits the expression of connexin 43 and gap junction per- meability in astrocytes, disturbs calcium homeostasis, and in- duces DNAdamage or inflammatoryresponsesanddisruptive effects on cell cycle 7779.As

56、a neurodegenerative model, rotenone has been used successfully in in vitro and in vivo studies of PD, due to the similaritybetween thecellularand moleculareffectsproduced by this toxin and the symptoms of PD 39, 62, 63, 80. For example, rotenone has been previously used in cell lines such as SH-SY5Y

57、 (human neuroblastoma) and animal models of PD 1, 5, 39, 62, 80. In this regard, it has been reported that in mice and rats, continuous administration of rotenone mimics some of the characteristics of PD, including selective degen- eration of dopaminergic neurons, mitochondrial dysfunction and incre

58、ased ROS production, astrocyte and microglial acti- vation, blood-brainbarrierdysfunction, formationofneuronal cytoplasmic inclusions, anxiety-like behavior, defects in spa- tial memory, and motor disorders 1, 5, 39, 72, 73, 8185. Finally, in a study by the National Institute of Health (NIH), it was observed that people with exposure to rotenone are 2.5 times more likely to develop PD than those who are unex- posed 80, and the use of gloves and other protective mea- sures is important to p