Enhanced synthesis of platelet-derived growth factor following injury induced by 6-hydroxydopamine in rat brain

Funa, Keiko; Yamada, Naoshi; Brodin, Greger; Pietz, Katja; Ahgrén, Aive; Wictorin, Klas; Lindvall, Olle; Odin, Per

doi:10.1016/0306-4522(96)00152-2

Cited by 33 publications

(20 citation statements)

References 45 publications

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“…EGFR is expressed in a wide variety of cells; however, we did not observe cribriform structures in lens epithelial cells (Bhuyan et al, 2000) or smooth muscle cells (Konishi and Berk, 2003). Although bFGF (Hou et al, 1995;Petersson et al, 2002;Madiai et al, 2003) and PDGF (Funa et al, 1996;Fruttiger et al, 1996;Luo and Miller, 1999) are also implicated in regulating the functions of astrocytes following CNS injury, these growth factors did not induce astrocytes to form cavernous spaces in our cultures. The EGFR pathway in astrocytes may be a specific, signal transduction pathway that regulates reactive astrocytes to form the cavernous spaces in glial scars after CNS injuries.…”

Section: Discussioncontrasting

confidence: 66%

Activation of epidermal growth factor receptor causes astrocytes to form cribriform structures

Liu

Neufeld

2004

Glia

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Epidermal growth factor receptor (EGFR) is expressed in reactive astrocytes following injury in the CNS. However, the effects of activation of the EGFR pathway in astrocytes are not well established. In the present study, we demonstrate that activation of EGFR causes optic nerve astrocytes, as well as brain astrocytes, to form cribriform structures with cavernous spaces. Formation of the cribriform structures is dependent on new protein synthesis and cell proliferation. Platelet-derived growth factor and basic fibroblast growth factor were not effective. Smooth muscle cells and epithelial cells do not form cribriform structures in response to EGFR activation. The formation of the cribriform structures appears to be related to a guided migration of astrocytes and the expression of integrin beta1 and extracellular fibronectin in response to activation of EGFR. The EGFR pathway may be a specific, signal transduction pathway that regulates reactive astrocytes to form cavernous spaces in the glial scars following CNS injury and in the compressed optic nerve in glaucomatous optic nerve neuropathy.

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Section: Discussioncontrasting

confidence: 66%

Activation of epidermal growth factor receptor causes astrocytes to form cribriform structures

Liu

Neufeld

2004

Glia

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“…Carvey et al (1989Carvey et al ( , 1996 have shown that adult striatal tissue contains a neurotrophic activity (active on DA neurons in culture) that is increased after lesion of the nigrostriatal afferents or blockade of DA receptors. The factor or factors involved have so far not been identified, but several growth factors with neurotrophic activity on DA neurons are known to be expressed at elevated levels in the DA-denervated striatum (Funa et al, 1996;Zhou et al, 1996; Figure 7. A, Nigral TH-positive cell number and striatal TH-positive innervation were highly correlated in the sham-operated and normal controls (dashed line; r ϭ 0.93, p Ͻ 0.0001), as well as in the grafted animals (r ϭ 0.62; p ϭ 0.01).…”

Section: Discussionmentioning

confidence: 99%

Growth and Functional Efficacy of Intrastriatal Nigral Transplants Depend on the Extent of Nigrostriatal Degeneration

2001

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Previous studies have shown that the functional efficacy of intrastriatal transplants of fetal dopamine (DA) neurons in the rat Parkinson model depends on their ability to establish a new functional innervation of the denervated striatum. Here we report that the survival, growth, and function of the grafted DA neurons greatly depend on the severity of the lesion of the host nigrostriatal system. Fiber outgrowth, and to a lesser extent also cell survival, were significantly reduced in animals in which part of the intrinsic DA system was left intact. Moreover, graftinduced functional recovery, as assessed in the stepping, pawuse, and apomorphine rotation tests, was obtained only in severely lesioned animals, i.e., in rats with Ͼ70% DA denervation of the host striatum. Functional recovery seen in these animals in which the 6-hydroxydopamine (6-OHDA) lesion was confined to the striatum was more pronounced than that previously obtained in rats with complete lesions of the mesencephalic DA system, indicating that spared portions of the host DA system, particularly those innervating nonstriatal forebrain areas, may be necessary for the grafts to exert their optimal functional effect. These data have implications for the optimal use of fetal nigral transplants in Parkinson patients in different stages of the disease.Key words: Parkinson's disease; transplantation; sensorimotor behavior; stepping; paw use; tyrosine hydroxylase; stereology Impairments in sensorimotor function induced by lesions of the nigrostriatal DA system can be reversed by intrastriatal transplants of nigral DA neurons taken from the fetal ventral mesencephalon (VM). However, functional recovery is incomplete: whereas some aspects of the DA deficiency syndrome are completely reversed (e.g., drug-induced turning behavior and sensorimotor neglect), other deficits, such as forelimb akinesia and skilled paw-use, are only partly or marginally affected by the grafted DA neurons (Björklund et al., 1994;Herman and Abrous, 1994;Winkler et al., 1999). The functional capacity of intrastriatal VM transplants is determined, at least in part, by the extent of striatal reinnervation provided by the grafted DA neurons and the placement of the cells, i.e., the subregion of the striatal complex reached by the graft-derived axons Mandel et al., 1990;Annett et al., 1995). Nevertheless, attempts to improve the functional efficacy of intrastriatal nigral transplants by multiple graft placements have so far been unsuccessful (Nikkhah et al., 1993;Olsson et al., 1995;Winkler et al., 1999). In these experiments the entire caudate putamen was reinnervated to a level of ϳ30 -80% of normal, but recovery of forelimb akinesia and paw use remained incomplete. These studies, however, were performed in rats with a complete unilateral 6-OHDAinduced lesion of the medial forebrain bundle (MFB), resulting in a widespread denervation of both striatal, limbic, and cortical areas. The functional impairments seen in these animals, therefore, reflect a combination of striatal and nonstria...

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“…No pathological changes were identified based on assessments of patients' visual acuity or perimetry. There was no indication of weight loss or nausea in neurons in vitro (5-7), and lesions in the mesostriatal dopaminergic system in vivo show evidence of elevated PDGF-B synthesis, which was interpreted as a possible endogenous neuroprotective response (8). Furthermore, recent animal studies demonstrated that intracerebroventricular (i.c.v.)…”

Section: Clinical Outcomesmentioning

confidence: 99%

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients

Paul¹,

Zachrisson²,

Varrone³

et al. 2015

J. Clin. Invest.

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BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS.We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS.All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen.CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.

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Enhanced synthesis of platelet-derived growth factor following injury induced by 6-hydroxydopamine in rat brain

Cited by 33 publications

References 45 publications

Activation of epidermal growth factor receptor causes astrocytes to form cribriform structures

Activation of epidermal growth factor receptor causes astrocytes to form cribriform structures

Growth and Functional Efficacy of Intrastriatal Nigral Transplants Depend on the Extent of Nigrostriatal Degeneration

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients

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