Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivo experimental models for hypoxia/ischemia

Kooij, Michael A. van der; Groenendaal, Floris; Kavelaars, Annemieke; Heijnen, Cobi J.; Bel, Frank van

doi:10.1016/j.brainresrev.2008.04.007

Cited by 136 publications

(102 citation statements)

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“…Effects were too small to demonstrate any gender effect with multiple regression analysis in the present study, although some studies in both animals and humans suggest that the neuroprotective effect of EPO may be gender dependent (14,17). EPO has been reported to have neuroprotective abilities via anti-inflammation, antiapoptosis, and neuroregeneration (10,11,23). Recently, EPO has been used in relatively high dosages (0.5-3 kU/kg) for at least three times in (preterm) infants, and improvement of long-term outcome was observed (24)(25)(26).…”

Section: Discussionmentioning

confidence: 53%

“…The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10)(11)(12)(13). In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14).…”

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confidence: 99%

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Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

et al. 2012

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Background: Both hypothermia and erythropoietin (ePO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (hI). We investigated a possible additive effect of the use of a combination of hypothermia-ePO in a rat model of neonatal hI. Methods: at postnatal day 7, rats were subjected to hI and then randomized to 3 h of hypothermia, ePO, or both. sensorimotor function was assessed by the cylinder-rearing test (cRT) at 2 and 5 wk after hI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. results: Multivariable analysis using general linear modeling showed that hypothermia, ePO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after hI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the cRT. Maximal improvement in males was 26% after combined treatment with hypothermia and ePO. histological outcome was improved by hypothermia only with no additional effect of ePO or gender. conclusion: hypothermia after hI improved sensorimotor function in females more than in males. There was a borderline additive effect of ePO when combined with hypothermia. histology of brain lesion volume and white matter damage was improved only by hypothermia.P erinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury and is associated with long-term neurological sequelae such as cognitive dysfunction, developmental delay, seizures, and sensory and/or motor impairment (1,2). Several studies in newborn rodents indicate that reduction of brain temperature by 2-5 °C even for 3 h, when started within 6 h after HI, provides neuroprotection and improved behavioral outcome (3-6).The neuroprotective effects of hypothermia of mildly asphyxiated newborns have been demonstrated, but in clinical practice, morbidity and mortality remain considerable (30-45%) (7,8). The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10-13). In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14). In recent studies with a rodent model, females appear to benefit more from neuroprotective interventions after HI, such as hypothermia, EPO,.The aim of the present study was to test whether the addition of EPO to hypothermia has additive neuroprotective effects as compared with a single treatment and to examine possible gender effects. Results HypothermiaSham-treated rats did not show a paw preference in the cylinder-rearing test (CRT) (paw preference < ±5%, data not shown). A significant paw preference of the unimpaired forepaw in the normothermia groups was observed at both 2 and 5 wk after HI (Figure 1). Differences between males and females in the normothermia group were not statistically significant. In fema...

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Section: Discussionmentioning

confidence: 53%

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confidence: 99%

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

et al. 2012

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“…Several investigations have established EPO as a neuroprotective agent, protecting multiple neuronal cell types from various injuries (Konishi et al, 1993;Sakanaka et al, 1998;Grimm et al, 2002Grimm et al, , 2004van der Kooij et al, 2008). Previously, our laboratory focused on delivery of a mutated form of erythropoietin (EPO) to rescue photoreceptor cells in a mouse model of retinal degeneration (Sullivan et al, 2011).…”

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Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

et al. 2011

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A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.

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“…Son y›llarda yap›lan araflt›rmalarda, oksijen ba¤›ml› sistemle yönetilen ve esas olarak böbreklerden sal›nan eritropoietinin (EPO) beyinde de üretildi¤i tespit edilmifltir (3,4). Hayvan deneylerinde, iskemi ve hipoksi sonras›nda beyin hücrelerinde EPO almaçlar›n›n (reseptörlerinin) artt›¤› gözlenmifl ayr›ca invitro ve invivo olarak yap›lan birçok çal›flmada EPO'nun nöronlar› korudu¤u tespit edilmifltir (5,6). Çal›flmalarda EPO'nun hücresel düzeyde, özellikle programl› hücre ölümünü azaltt›¤›, kapiler oluflumlar› sa¤lad›¤›, dopamin gibi hücreleri koruyan nörotransmiterlerin sal›n›m›n› uyard›¤›, serbest oksijen radikalleri, nitrik oksit ve enflamatuar arac›lar›n sal›n›m›n› azaltt›¤›, hücre içi kalsiyumu düzenle-di¤i, kainik asit toksisitesini önledi¤i gösterilmifltir (6).…”

Section: Giriflunclassified

“…Çal›flmalarda EPO'nun hücresel düzeyde, özellikle programl› hücre ölümünü azaltt›¤›, kapiler oluflumlar› sa¤lad›¤›, dopamin gibi hücreleri koruyan nörotransmiterlerin sal›n›m›n› uyard›¤›, serbest oksijen radikalleri, nitrik oksit ve enflamatuar arac›lar›n sal›n›m›n› azaltt›¤›, hücre içi kalsiyumu düzenle-di¤i, kainik asit toksisitesini önledi¤i gösterilmifltir (6). Beyinde bulunan EPO ve EPO almaç sisteminin hipoksi ve iskemi sonras› beyni korumaya yönelik etkisi gösterdi¤inin bulunmas› üzerine yenido¤an›n H‹E tedavisinde EPO kullan›m› gündeme gelmifltir (5)(6)(7)(8)(9).…”

Section: Giriflunclassified

Yenidoğanlarda hipoksik-iskemik ansefalopati evresi ile eritropoietin düzeyleri arasındaki ilişki: Tedavide kullanılabilir mi?

Özdemır¹

2010

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Y Ye en ni id do o¤ ¤a an nl la ar rd da a h hi ip po ok ks si ik k--i is sk ke em mi ik k a an ns se ef fa al lo op pa at ti i e ev vr re es si i i il le e e er ri it tr ro op po oi ie et ti in n d dü üz ze ey yl le er ri i a ar ra as s› ›n nd da ak ki i i il li ifl flk ki i: : T Te ed da av vi id de e k ku ul ll la an n› ›l la ab bi il li ir r m mi i? ?T Th he e r re el la at ti io on ns sh hi ip p b be et tw we ee en n g gr ra ad de e o of f h hy yp po ox xi ic c--i is sc ch ha ae em mi ic c e en nc ce ep ph ha al lo op pa at th hy y a an nd d e er ry yt th hr ro op po oi ie et ti in n l le ev ve el ls s i in n t th he e n ne ew wb bo or rn n: : C Ca an n i it t b be e u us se ed d i in n t tr re ea at tm me en nt t? ?Y Ya as se em mi in n A Al lt tu un ne er r T To or ru un n, , A Ay yl li in n ‹ ‹n na al l* *, , M Me eh hm me et t A Ak ki if f Ö Öz zd de em mi ir r* ** *, , T Tu ur rk ka an n P Pa at t› ›r ro o¤ ¤l lu u* ** *, , M Mu us sa a K Ka ar ra ak kü ük kc cü ü* ** * Ö Öz zg gü ün n A Ar ra afl flt t› ›r rm ma a O Or ri ig gi in na al l A Ar rt ti ic cl le e Ö Öz ze et t Amaç: Yenido¤an hipoksik iskemik ansefalopatisi ciddi bir hastal›¤a ve ölüme sebep olmas›na ra¤men günümüzde etkin bir tedavisi yoktur. Eritropoietin hipoksik iskemik beyin zedelenmesinden sonra ifllevsel olarak iyileflme sa¤lad›¤› gösterilmesine ra¤men uygulama zaman› ve uygun doz uygulamas› tam olarak ortaya ç›kar›lamam›flt›r. Bu çal›flman›n amac› asfiktik yenido¤anlarda hipoksinin fliddeti ve serum eritropoietin seviyesini karfl›laflt›rmak ve bu iliflkinin klinik kullan›m aç›s›ndan önemini de¤erlendirmektir. Gereç ve Yöntem:Eritropoietin düzeylerini do¤um sonras› 0, 12, 24, 36, ve 48. saatlerde enzim immün yöntemi ile dört grupta ölçtük. Bu gruplar (1) evre 1 (n=11); (2) evre 2 (n=9); (3) evre 3 hipoksik iskemik ansefalopatisi olan yenido¤anlar (n=8) ve sa¤l›kl› kontrol grubundan (n=10) oluflmakta idi. Bulgular:Kontrol grubunda eritropoietin düzeyinin geometrik ortalamas› 5 mU/mL idi. Eritropoietin seviyeleri 0 ve 12 saatte grup 2 ve 3'de kontrol ve grup 1'e göre; 24 ve 36. saatlerde ise grup 3'de di¤er gruplara göre istatistiksel olarak anlaml› derecede yüksekti (p=0,01). Kontrol ve hipoksik iskemik ansefalopati gruplar›nda 48. saatte fark yoktu (p>0,05). Ç›kar›mlar:Bu sonuçlara göre zaman›nda do¤an yenido¤anlarda rekombinan insan eritropoietin tedavisinin orta derece hipoksik iskemik ansefalopatide 12 saat, a¤›r olgularda 24 saat sonra kullan›lmas› gerekti¤ini düflünmekteyiz. (Türk Ped Arfl 2010; 45: 334-8) Anahtar sözcükler: Eritropoietin, hipoksik-iskemik ansefalopati, yenido¤an S Su um mm ma ar ry y Aim: Neonatal hypoxic-ischemic encephalopathy leads to mortality and severe morbidity, but currently there is no effective treatment. Erythropoietin has been well characterized and shown to improve functional outcomes after hypoxic-ischemic brain injury; however, application time and optimal dosing regimens have not been clarified. The purpose of this study was to compare the severity of hypoxia with serum erythropoietin level...

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Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivo experimental models for hypoxia/ischemia

Cited by 136 publications

References 103 publications

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

Yenidoğanlarda hipoksik-iskemik ansefalopati evresi ile eritropoietin düzeyleri arasındaki ilişki: Tedavide kullanılabilir mi?

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