Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
NEUROTROPHIC FACTORS IN THE THERAPY OF PARKINSON’S DISEASE Fabrizio Facchinetti, Salvatore Te rr a z z i n o , Antonello D’Arrigo, Luciano Rinaldi, Alberta Leon Research & Innovation, Padua Reprint requests to: Dr Fabrizio Facchinetti, Research & Innovation, Via Svizzera 16, 35127 Padua, Italy. e-mail: [email protected] Many environmental and occupational chemicals are known to affect the central and/or peripheral nervous system, causing changes that may result in neurological and psychiatric disorders. Because of the limited accessibility of the mammalian nervous tissue, new strategies are being developed to identify biochemical parameters of neuronal cell function, which can be measured in easily obtained tissues, such as blood cells, as potential markers of the chemically-induced alterations occurring in the nervous system. This review includes a comparative analysis of the effects of mercurials on calcium signalling in the neuroadrenergic PC12 cells and rat splenic T lymphocytes in an attempt to characterize this second messenger system as a potential indicator of subclinical toxicity. The suitability of neurotransmitter receptors in blood cells, such as the sigma binding sites, as biological markers of psychiatric disorders is also discussed. KEY WORDS: Brain-derived neurotrophic factor (BDNF), dopaminergic neurons, gene therapy, glial cell line-derived neurotrophic factor (GDNF), neurotrophic factors (NTs), Parkinson’s disease. FUNCT NEUROL 2001;16: 45-56 INTRODUCTION Neurotrophic factors (NTs) are secreted proteins that regulate survival and differentiation of nerve cells. Nerve growth factor (NGF), the first discovered NT, together with brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), form the classical family of NTs. However, many other growth factors, which are effective also outside the nervous system, such as glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor (IGF I), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF) and members of the tumor growth factor-beta (TGF-beta) superfamily, fulfill the functional definition of “neurotrophic factors”. NTs were originally identified as target-derived compounds regulating neuronal survival, growth and differentiation during development. In the adult brain, NTs are necessary to maintain neuronal function and phenotype. Increased expression of NTs is a common response to brain damage (1) that may have a neuroprotective role given the ability of NTs to protect neurons against free radical damage, excitotoxicity and apoptosis (2). Idiopathic Parkinson’s disease (PD) is a neurodegenerative disorder pathologically de- FUNCTIONAL NEUROLOGY (16)1 2001 45 F. Facchinetti et al. fined by a selective loss of dopaminergic (DA) neurons in the pars compacta of the substantia nigra (SNc). Despite the great research efforts of the last decade, the etiopathogenesis of PD is still unknown. L-dopa and DA agonists are currently used to alleviate symptoms of PD, but most treated patients still develop a progressive functional disability that severely affects their quality of life. Given the progressive nature of nigrostriatal degeneration in PD, therapeutic agents capable of slowing down or blocking this process could be clinically significant. It has been postulated that loss of DA neurons in PD may be accompanied by insufficient trophic support leading to neuronal apoptosis. However, it is not clear whether neuronal death is predominantly apoptotic in PD, or whether a reduced neurotrophic support is involved in the neuronal loss accompanying the disease in humans. Regardless of the causes of PD, NTs, by promoting DA neuronal growth and function and by interfering with neurotoxic processes, could be of therapeutic value. THE GDNF FAMILY Glial cell line-derived neurotrophic factor was the first identified member of a family of factors, which includes neurturin (NTN), enovin and artemin (ART), all of which are distant members of the transforming growth factor-beta (TGF-beta) superfamily. GDNF was purified and cloned from a rat glial cell line as a released trophic factor specific for cultured primary DA neurons (3). In addition, GDNF family proteins are potent survival factors for several populations of central and peripheral neurons. At present, GDNF appears to be the most promising trophic factor in the therapy of PD. Glial cell line-derived neurotrophic factor family members (GFMs) bind to a receptor complex formed by a binding component, the glycosyl-phosphatidyl inositol (GPI)-anchored GDNF family receptor (GFR), and a signalling compo- 46 FUNCTIONAL NEUROLOGY (16)1 2001 nent, the receptor tyrosine kinase Ret (for a review, see 4). According to one model of GDNF signalling, GFR would appear to be involved in GDNF binding with no intrinsic signalling ability, whereas Ret would appear to be responsible for the intracellular signalling, but unable to bind the factor in the absence of GFR. The importance of GFMs and their receptors in the nigrostriatal circuit is well reflected by their expression in that area. GDNF and NTN are both present in developing striatal neurons and GDNF mRNA has been detected in both cholinergic and GABAergic interneurons of the striatum (5). In the SNc, GDNF mRNA is detectable in the majority of DA neurons. The mRNA for the Ret receptor has also been found in nigral DA neurons, whereas there is no clear indication of its presence in the striatum. GFR receptors show a distinct, albeit overlapping distribution, being expressed both by nigral DA neurons and, to some extent, also in the ventral striatum (6). Effects of GDNF on DA neurons in culture Glial cell line-derived neurotrophic factor has the ability, in combination with other factors, to convert rat fetal (E14.5) mesencephalic progenitor cells into tyrosine hydroxylase (TH)-immunoreactive neurons in vitro (7). In embryonic midbrain cultures, GDNF promotes the survival and inhibits the apoptosis of DA neurons (8). It also promotes the biochemical and morphological differentiation of cultured ventral mesencephalic neurons by producing a significant increase in the number of neurite-bearing cells as well as in the extent of their fiber network (9). These effects are specific as GDNF does not increase total neuron or astrocyte numbers nor does it increase transmitter uptake by GABAcontaining and serotonergic neurons (3). In addition, GDNF protects cultured DA neurons from the neurotoxic effects of 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) (9), and 6-hydroxydopamine (6-OHDA) (10). As exemplified in Table I, GDNF robustly promotes the survival Neurotrophic factors in the therapy of Parkinson’s disease Table I - Overview of the effects of various neurotrophic factors on ventral mesencephalic neurons in culture NTs GDNF NTN BDNF NT-3 NT-4/5 NGF bFGF* Survival Neuritogenesis Dopaminergic phenotype Neuroprotection +++ +++ +++ ++ +++ – +++ +++ NR ++ ++ +++ – + +++ NR ++ ++ – – ++ +++ NR +++ NR NR NR ++ References 3, 8-10 26 50 29 29 51 39 The degree of efficacy in promoting survival, neuritogenesis, dopaminergic phenotype and neuroprotection is expressed in arbitrary units where +++ = highest efficacy, and – = no efficacy. Abbreviations and symbols: * = effect largely mediated via stimulation of astroglia; NTs = neurotrophic factors; GDNF = glial cell linederived neurotrophic factor; NTN = neurturin; BDNF = brain-derived neurotrophic factor; NT-3 = neurotrophin-3; NT-4/5 = neurotrophin-4/5; NGF = nerve growth factor; bFGF = basic fibroblast growth factor; NR = not reported. and differentiation of midbrain DA neurons in culture providing thereby the rationale for its application in animal models of PD. The effects of GDNF in animal models of PD Protection of midbrain DA neurons by GDNF administration has been reported both in rodent and in non-human primate animal models of PD. In rats, the neuroprotective and/or behavioral effects of GDNF have been observed following: i) intranigral injections of 6-OHDA (11), ii) intrastriatal injection of 6-OHDA (12), iii) neurotoxic doses of methamphetamine and MPTP (13) and iv) axotomy-induced degeneration of the medial forebrain bundle (14). Appropriate administration appears the crucial issue in order to achieve maximal survival and trophic effects on nigrostriatal DA pathway and longterm behavioral motor recovery. Rats that receive unilateral 6-OHDA lesions can be induced to turn repetitively in circles in a direction either ipsilateral or contralateral to the lesion using amphetamine or apomorphine, respectively. Glial cell line-derived neu- rotrophic factor, when intracerebroventricularly injected, can access basal ganglia structures and have beneficial, although transient, effects on drug-induced rotational behavior (15). In the MPTP-lesioned rhesus monkey, GDNF intracerebrally injected, either alone or in combination with L-dopa and carbidopa, improves bradykinesia, rigidity and postural instability (16). Intrastriatal GDNF treatment in parkinsonian rats preserves the nigrostriatal DA system and increases axonal sprouting and reinnervation of deafferented striatum to a degree sufficient to reverse spontaneous motor deficits (17). On the other hand, intranigral GDNF administration increases nigral DA neuron survival but does not prevent striatal terminal degeneration in 6-OHDA-lesioned rats (12,15). Repeated nigral GDNF injections lead neither to significant reinnervation of the lesioned striatal target nor to a behavioral recovery (12). Taken together, these results indicate that the striatum is a more suitable site for GDNF administration than the SNc in order to prevent DA terminals from degeneration and/or to facilitate behavioral recovery from motor asymmetry. FUNCTIONAL NEUROLOGY (16)1 2001 47 F. Facchinetti et al. Table II - Overview of the effects of neurotrophic factors on the nigrostriatal DA pathway in animal models of PD NTs GDNF NTN NBN/ART BDNF NT-3 NT-4/5 aFGF bFGF Survival Neuritogenesis Dopaminergic phenotype Behavioral recovery References +++ +/+++ ++ ++ ++ ++ + + +++ – NR ++ – ++ – + +++ +/ – ++ – – NR + NR +++ +/– NR ++ – ++ + + 17 26, 51–53 27 23, 36 24, 38 38 54, 55 56 The degree of efficacy in promoting survival, neuritogenesis, dopaminergic phenotype and behavioral recovery is expressed in arbitrary units, where +++ = highest efficacy and – = no efficacy. Abbreviations: NTs = neurotrophic factors; GDNF = glial cell line-derived neurotrophic factor; NTN = neurturin; NBN/ART= neublastin/artemin; BDNF = brain–derived neurotrophic factor; NT-3 = neurotrophin-3; NT-4/5 = neurotrophin-4/5; aFGF = acidic fibroblast growth factor; bFGF= basic fibroblast growth factor; NR: not reported. As exemplified in Table II, GDNF can have potent effects on DA survival, phenotype and motor behavioral recovery in animal models of PD. Despite these results, the main concern as regards the applicability of GDNF in PD is the need to inject repeatedly large amounts of the peptide directly into the brain in order to obtain clinically significant effects. GDNF in gene therapy The possibility of expressing NTs locally in specific brain areas may avoid potential side effects related to the activation of other brain structures. The introduction of specific therapeutic genes into target brain areas is possible by means of viral vector-mediated direct transfer. This genetic approach obviates the need for high doses and repeated administrations. Therefore, gene transfer based on viral vectors expressing NTs is currently under extensive investigation in animal models of PD. Striatal injection of adenovirus (Ad) vectorexpressing GDNF significantly prevents degeneration of the nigrostriatal DA pathway and reduces amphetamine-induced turning behavior in 6-OHDA- or MPTP-lesioned rats (18). The differential effects of injecting Ad-GDNF near either nigrostriatal DA cell bodies or DA terminals has been 48 FUNCTIONAL NEUROLOGY (16)1 2001 compared in aged rats. While similar protection of nigral DA neurons is observed, only striatal GDNF injection protects striatal DA nerve terminals against 6-OHDA-induced damage and prevents behavioral deficits characteristic of unilateral DA depletion (19). Taken together, these reports provide support for a potential therapeutic value of GDNF expression driven by adenoviral vectors in the attempt to prevent further cell death and/or enhance the DA tone of surviving neurons in PD. However, lack of sustained transgene expression, high immunogenicity and potential toxicity may limit the use of adenoviral vectors, at least those of the first generation, for clinical purposes. Recent developments in lentiviral and recombinant adeno-associated viral vectors (rAAV) have resulted in transgene expression within the CNS detectable for more than 6 months after injection without cytotoxicity (20). A single administration of rAAV-expressing GDNF enhances nigral DA survival both before and after a striatal 6-OHDA lesion (21). Protection of nigral DA neurons in medial forebrain bundle (MFB)-axotomized rats is also obtained after nigral injection of self-inactivating modified lentiviral vector-expressing GDNF (22). Hence, GDNF gene therapy based on novel viral vectors could, potentially, fulfill most of the requirements to qualify as therapeutically relevant for PD: i) biological efficacy; ii) long- Neurotrophic factors in the therapy of Parkinson’s disease term expression; iii) lack of toxicity coupled with a wide therapeutic window. However, further studies are still necessary to evaluate long-term safety. GDNF in cell replacement therapy The ability of GDNF to regulate developmental neuron survival and differentiation of DA neurons may be used to enhance the success of cerebral grafts and to induce stem cells to phenotypically differentiate into DA neurons. GDNF administration adjacent to the embryonic DA graft not only increases graft survival but also restores the nigrostriatal DA pathway in unilateral 6-OHDA-lesioned rats, thus leading to a lasting decrease in drug-induced rotational behavior (23). Pre-treatment with GDNF is also effective in increasing graft-derived fiber outgrowth and improving contralateral forelimb function and amphetamine-induced rotational behavior in unilateral 6-OHDA-lesioned rats (24). Co-graft of a GDNF-secreting Schwann cell line with embryonic ventral mesencephalic cells improves graft survival and promotes neurite outgrowth into the host neuropil as well as axonal growth in the striatum (25). Taken together, these reports suggest that GDNF could be effectively used in conjunction with cell replacement therapies. GDNF-related NTs Neurturin is expressed in the nigrostriatal system, and it exerts potent effects on survival and function of midbrain DA neurons. NTN mRNA is sequentially expressed in the ventral midbrain and striatum during development and supports survival of cultured embryonic DA neurons (6). The structural homology and the similar potency and efficacy of NTN and GDNF in promoting DA neuron survival (Tables I and II) suggest that GDNF and NTN may exert redundant trophic influences on nigral DA neurons (26). To date, there are contrasting reports on the effectiveness of NTN in PD animal models, probably due to the different experimental conditions adopted (Table II). Recently, new GDNF-family members, such as neublastin (NBN) (27), identical to ART, have been cloned. As with GDNF, protection of nigral DA neurons has been reported both in vitro and in vivo (27). However, further investigations are necessary to clarify whether NTN and NBN/ART might be considered potential therapeutic agents in PD. CLASSICAL NTs All the NTs belonging to the NGF family bind to the p75 NTR low-affinity receptor, but their ligand specificity is determined by binding activating transmembrane receptor tyrosine kinases, the trks. NGF acts through trkA; BDNF and NT 4/5 act through trkB whereas NT-3 acts through trkC and, less potently, through trkA and trkB. In adult CNS, p75NTR receptor, which is related to proteins belonging to the tumor necrosis receptor-alpha family, appears to be mainly coexpressed with trkA. When not associated with trk receptors, p75NTR can mediate neuronal death (28). mRNAs encoding trkB and trkC, the functional high-affinity receptors for BDNF, NT-4/5 and NT-3 respectively, are expressed in the SN of the adult rat brain, as well as in cultures of developing ventral mesencephalon. The NGF receptor trkA is not expressed in ventral mesencephalic DA neurons and NGF appears to be only a weak trophic factor for DA neurons, most likely acting through indirect mechanisms. BDNF Among the NTs, BDNF is considered an interesting candidate for the development of therapeutic strategies applicable in PD (Table II). BDNF promotes the survival, morphological and biochemical differentiation of DA neurons in fetal midbrain cultures (29). In addition, BDNF protects DA neurons from the neurotoxic effects of MPP+ and 6-OHDA (30). The distribution of BDNF and its high-affinity receptor, trkB, in the nigrostriatal system suggests a critical role of this neurotrophin in the survival of different resident neuronal populations. FUNCTIONAL NEUROLOGY (16)1 2001 49 F. Facchinetti et al. TrkB mRNA has been found in both cholinergic and GABAergic striatal interneurons (31). The expression pattern of BDNF and trkB in the striatum has suggested that BDNF could act both as a target-derived trophic factor for DA neurons projecting from the SNc, and as an autocrine factor affecting the survival of neurons within the striatum itself. In the SNc, the mRNAs of both BDNF and trkB have been detected in DA neurons (32). The co-expression in nigral DA neurons of BDNF and trkB supports the idea that BDNF can affect neuronal survival by both paracrine and autocrine mechanisms. Several groups have investigated the survival-promoting effects of BDNF on the nigrostriatal DA pathway and its capacity to prevent behavioral motor asymmetries in animal models of PD (Table II). In parkinsonian rats, prevention of nigral cell loss is observed both after supranigral injection of engineered BDNF secreting fibroblasts (33) and after three-week infusion of BDNF in the SNc (34). Intrastriatal grafts of engineered fibroblast- or astrocyte-expressing BDNF partially prevent nigrostriatal DA degeneration without affecting tyrosine hydroxylase-immunoreactive (TH-IR) nerve terminals of 6-OHDA-lesioned rats (35). The effects of BDNF appear to be more transient than those of GDNF, since decrease in rotational behavior and KCl-induced DA release is observed in rats 1-3 months after the administration of GDNF- but not of BDNF-bridged grafts (23). Administration of rAAV-expressing BDNF in the SN of 6-OHDA-lesioned rats reduces amphetamine-induced turning behavior but does not, in spite of long-term transgene expression, affect the number of nigral TH-labeled neurons (36). Thus, although BDNF is as effective as GDNF in promoting DA neuronal survival, it is not as effective as GDNF in inducing and maintaining the DA phenotype (Table II). NT-3 and NT-4/5 NT-3, which acts through the trkC receptor, has broadly similar effects to BDNF in promoting 50 FUNCTIONAL NEUROLOGY (16)1 2001 the survival and differentiated phenotype of cultured DA neurons. Although BDNF and NT-4/5 are thought to act through the same high-affinity receptor (trkB), these two NTs have distinct as well as overlapping actions in vitro. For instance, NT-4/5 had no effect, in marked contrast to BDNF and NT-3, on the DA uptake capacity of cultured mesencephalic neurons (37). In addition, these factors appear less promising than GDNF (Table II) in experimental animal models of PD. While NT-3 and NT-4/5 are nearly as effective as GDNF in promoting DA neuronal survival, they are less effective than GDNF in promoting functional and behavioral recovery (24, 38). OTHER TROPHIC FACTORS In addition to GDNF and certain NTs belonging to the classical NT family, basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGF-alpha), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB) and growth/differentiation factor 5 (GDF5), have proven to increase DA neuron survival in cultured mesencephalic neurons. As exemplified in Table II, in experimental animal models of PD, bFGF and acidic fibroblast growth factor (aFGF) appear to be moderately effective in promoting functional and behavioral recovery. However, bFGF, EGF, PDGF-BB, GDF5 and TGF-alpha effects are predominantly indirect, as they occur mainly through the stimulation of glial cell division and release of trophic factors (39). NTs in PD In spite of the bulk of preclinical research conducted so far, the few studies concerning NTs in human CNS are rather scattered and do not shed any light on the role of NTs and their receptors in PD (40,41). A number of clinical trials have either been conducted or are ongoing to evaluate the safety and the therapeutic benefits of Neurotrophic factors in the therapy of Parkinson’s disease NTs in clinical settings associated with loss of neuronal function, including neurodegenerative diseases (see Table III). So far, only GDNF has been tested in PD patients: more specifically, while a case report showed no benefit and severe side effects following intracerebroventricular injections of GDNF in a patient with PD (42), GDNF exposure of fetal DA cells, prior to putaminal implant, was reported to enhance graft survival in two patients with PD (43). These preliminary results raise the possibility that NTs may perhaps be employed to promote a better graft survival in the surgical approach to PD treatment. CONCLUSIONS Since certain NTs, in particular GDNF and BDNF, are neuroprotective in animal models of PD, the rationale for developing therapies involv- ing the use of native or recombinant NTs is strong. However, it is not known how closely neurotoxin-induced lesions mimic the state of diseased neurons in human PD. While in experimental animals a PD-like syndrome is obtained through an acute chemical insult (MPTP or 6OHDA), the naturally occurring disease is, in contrast, a slow and progressive process due to unknown causes. Thus, benefits observed in animal models with the use of NTs may not necessarily be reproduced in clinical trials. In addition, beneficial effects could be hampered by potentially occurring side effects consequent to a chronic treatment (e.g., aberrant neuritic outgrowth, increased function of other responsive neuronal populations, peripheral effects). Lastly, recent clinical trials with NTs in other neurodegenerative diseases have been disappointing; e.g., GDNF did not appear to be beneficial in amyotrophic lateral sclerosis (ALS) patients and, in Table III - Overview of the clinical effects of neurotrophic factors in neurodegenerative diseases Disease NTs Trials/clinical cases Status/outcome References Parkinson’s disease (PD) – GDNF(i.c.v.) – Human fetal – nigra+GDNF – Case report – 2 cases – Severe side effects – Enhanced graft – survival 42 43 Amytrophic lateral sclerosis (ALS) – GDNF – BDNF (s.c.) – BDNF (i.t.) – BDNF(s.c.high dose) – CNTF (s.c.) – Phase II – Phase III – Phase II – Phase II – Phase II – Discontinued – No efficacy – Ongoing – Ongoing – Discontinued (S.E.) http://www.amgen.com 57 57 57 58 Diabetic neuropathy NGF (s.c.) Phase III No efficacy http://www.gene.com 59 Alzheimer’s disease NGF 3 cases ? (Hyperalgesia) 60 Constipation (spinal cord injury) NT-3 Phase II Ongoing http://www.amgen.com Immunophilins (p.o.) Phase I Ongoing http://www.amgen.com PD ALS Abbreviations: NTs = neurotrophic factors; GDNF = glial cell line-derived neurotrophic factor; BDNF = brain-derived neurotrophic factor; CNTF = ciliary neurotrophic factor; NGF = nerve growth factor; NT-3 = neurotrophin-3; i.c.v. = intracerebral ventricular; s.c. = subcutaneous; i.t. = intrathecal; P.O. = per os. FUNCTIONAL NEUROLOGY (16)1 2001 51 F. Facchinetti et al. fact, displayed an array of side effects, while trials conducted with BDNF have not been satisfactory. These failures may, at least in part, be the consequence of the poor pharmacological properties of NTs (e.g. short in vivo half-lives due to protein degradation, low blood brain barrier permeability) (44). On the other hand, to improve CNS delivery and avoid some of the unwanted effects of systemic administration of NTs, gene therapy techniques have recently been developed and tested in animal models. The use of recombinant viruses to deliver GDNF or other NTs could avoid repeated invasive intracerebral procedures. Yet, several improvements are needed in current gene therapy technology: in safety, cell specificity, stability and possibility of regulation of gene expression. Neurotrophic factors could also be used in combination with other therapeutic strategies such as, for instance, cell replacement interventions. In fact, one limitation of grafting fetal neural tissue or expanded populations of human CNS progenitor cells into the brain is the relatively poor survival of the implanted cells. The ability of GDNF and BDNF to regulate the survival and differentiation of developing DA neurons can be used to enhance the success of cerebral grafts and/or to induce stem cells to phenotypically differentiate into DA neurons. Additionally, GDNF can be delivered by inserting into the striatum cells engineered to produce GDNF (45). A further way to overcome some of the problems linked to the therapeutic use of NTs might be the employment of low molecular weight compounds, either possessing intrinsic neurotrophic activity or capable of modulating the synthesis, release or signalling properties of endogenous NTs in the nigrostriatal system. Potential candidates include immunophilins (46), and NT mimetics. To date, however, no data is available on the possibility of producing low molecular weight compounds capable of mimicking the activity of GDNF or BDNF. Although this is due to the relatively poor information as regards the 52 FUNCTIONAL NEUROLOGY (16)1 2001 molecular details of their binding to receptors, the recent reports on NT mimicry strategies conducted in the field of NGF suggest that such an approach is feasible. For example, small cyclic peptides, capable of mimicking NGF β-turn structures that bind specifically to the trkA receptor, behave as trkA antagonists by competing with NGF for high affinity binding sites (47), while non-peptidic small molecule β-turn analogs of an anti-trkA monoclonal antibody have been reported to function as specific trkA agonists (48). To circumvent the problem of molecular instability, D-amino acid peptido-mimetics, more proteaseresistant than L-amino acid peptides and with longer half-lives, may be soon available (49). In addition, the development of agents capable of specifically modulating p75NTR receptor activity, without affecting the survival promoting functions of trks, may be relevant for the treatment of neurodegenerative disorders, in which uncontrolled apoptotic processes may be implicated. Thus, receptor or ligand modeling may give way, also in the case of BDNF or GDNF, to approaches similar to those mentioned above for NGF, with the aim of obtaining a fine tuning of neurotrophic activity in PD. Taken together, the experimental evidence here reviewed suggests that NTs and their receptors, in particular GDNF and BDNF, may be important therapeutic targets in PD. Unfortunately, to date, none of the identified NTs is specific for DA neurons and all of them, on the other hand, can elicit a wide variety of effects. Therefore, further knowledge regarding the potential consequences of prolonged exposure to “therapeutic” doses of NTs is needed. It will also be necessary to develop ways of efficiently delivering NTs to the brain and/or of locally stimulating their synthesis or of mimicking their activity. Hopefully, future research linking functional genomics with structural molecular chemistry may allow the design of drugs (e.g. small molecules, peptide mimetics) capable of modulating and/or mimicking specific functions of defined NTs in PD. Neurotrophic factors in the therapy of Parkinson’s disease REFERENCES 11. Hughes PE, Alexi T, Walton M et al. Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system. Prog Neurobiol 1999;57:421-450 12. Mattson MP, Lovell MA, Furukawa K, Markesbery WR. Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 1995;65:1740-1751 13. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993;260:1130-1132 14. Baloh RH, Enomoto H, Johnson EM Jr, Milbrandt J. The GDNF family ligands and receptors - implications for neural development. Curr Opin Neurobiol 2000;10:103110 15. Bizon JL, Lauterborn JC, Gall CM. Subpopulations of striatal interneurons can be distinguished on the basis of neurotrophic factor expression. J Comp Neurol 1999;408:283298 16. Widenfalk J, Nosrat C, Tomac A, Westphal H, Hoffer B, Olson L. Neurturin and glial cell line-derived neurotrophic factor receptor-beta (GDNFR-beta), novel proteins related to GDNF and GDNFR-alpha with specific cellular patterns of expression suggesting roles in the developing and adult nervous system and in peripheral organs. J Neurosci 1997;17:8506-8519 17. Potter ED, Ling ZD, Carvey PM. Cytokineinduced conversion of mesencephalic-derived progenitor cells into dopamine neurons. Cell Tissue Res 1999;296:235-246 18. Burke RE, Antonelli M, Sulzer D. Glial cell line-derived neurotrophic growth factor inhibits apoptotic death of postnatal 19. 10. 11. 12. 13. 14. 15. 16. 17. substantia nigra dopamine neurons in primary culture. J Neurochem 1998;71:517525 Hou JG, Lin LF, Mytilineou C. Glial cell line-derived neurotrophic factor exerts neurotrophic effects on dopaminergic neurons in vitro and promotes their survival and regrowth after damage by 1-methyl-4phenylpyridinium. J Neurochem 1996;66:7482 Kramer BC, Goldman AD, Mytilineou C. Glial cell line derived neurotrophic factor promotes the recovery of dopamine neurons damaged by 6-hydroxydopamine in vitro. Brain Res 1999;851:221-227 Choi-Lundberg DL, Lin Q, Chang YN et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 1997;275:838-841 Winkler C, Sauer H, Lee CS, Bjorklund A. Short-term GDNF treatment provides longterm rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 1996;16:7206-7215 Tomac A, Lindqvist E, Lin LF et al. Protection and repair of the nigrostriatal dopamine rgic system by GDNF in vivo. Nature 1995;373:335-339 Beck KD, Valverde J, Alexi T et al. Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature 1995;373:339-341 Lapchak PA, Miller PJ, Collins F, Jiao S. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery. Neuroscience 1997;78:61-72 Gash DM, Zhang Z, Ovadia A et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 1996;380:252255 Rosenblad C, Martinez-Serrano A, Bjork- FUNCTIONAL NEUROLOGY (16)1 2001 53 F. Facchinetti et al. 18. 19. 20. 21. 22. 23. 24. 54 lund A. Intrastriatal glial cell line-derived neurotrophic factor promotes sprouting of spared nigrostriatal dopaminergic afferents and induces recovery of function in a rat model of Parkinson’s disease. Neuroscience 1998;82:129-137 Bilang-Bleuel A, Revah F, Colin P et al. Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease. Proc Natl Acad Sci USA 1997;94:8818-8823 Connor B, Kozlowski DA, Schallert T, Tillerson JL, Davidson BL, Bohn MC. Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat. Gene Ther 1999;6:1936-1951 Snyder RO. Adeno-associated virus-mediated gene delivery. J Gene Med 1999;1:166175 Mandel RJ, Snyder RO, Leff SE. Recombinant adeno-associated viral vector-mediated glial cell line-derived neurotrophic factor gene transfer protects nigral dopamine neurons after onset of progressive degeneration in a rat model of Parkinson’s disease. Exp Neurol 1999;160:205-214 Deglon N, Tseng JL, Bensadoun JC et al. Self-inactivating lentiviral vectors with enhanced transgene expression as potential gene transfer system in Parkinson’s disease. Hum Gene Ther 2000;11:179-190 Tang FI, Tien LT, Zhou FC, Hoffer BJ, Wang Y. Intranigral ventral mesencephalic grafts and nigrostriatal injections of glial cell line-derived neurotrophic factor restore dopamine release in the striatum of 6-hydroxydopamine-lesioned rats. Exp Brain Res 1998;119:287-296 Espejo M, Cutillas B, Arenas TE, Ambrosio S. Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or FUNCTIONAL NEUROLOGY (16)1 2001 25. 26. 27. 28. 29. 30. 31. 32. glial cell line-derived neurotrophic factor. Cell Transplant 2000;9:45-53 Wilby MJ, Sinclair SR, Muir EM et al. A glial cell line-derived neurotrophic factor-secreting clone of the Schwann cell line SCTM41 enhances survival and fiber outgrowth from embryonic nigral neurons grafted to the striatum and to the lesioned substantia nigra. J Neurosci 1999;19:2301-2312 Horger BA, Nishimura MC, Armanini MP et al. Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. J Neurosci 1998;18:4929-4937 Rosenblad C, Gronborg M, Hansen C et al. In vivo protection of nigral dopamine neurons by lentiviral gene transfer of the novel GDNF-family member neublastin/artemin. Mol Cell Neurosci 2000;15:199-214 Casaccia-Bonnefil P, Gu C, Khursigara G, Chao MV. p75 neurotrophin receptor as a modulator of survival and death decisions. Microsc Res Tech 1999;45:217-224 Ventimiglia R, Mather PE, Jones BE, Lindsay RM. The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur J Neurosci 1993;7:213-222 Son JH, Chun HS, Joh TH, Cho S, Conti B, Lee JW. Neuroprotection and neuronal differentiation studies using substantia nigra dopaminergic cells derived from transgenic mouse embryos. J Neurosci 1999;19:10-20 Boissiere F, Faucheux B, Agid Y, Hirsch EC. Expression of catalytic trkB gene in the striatum and the basal forebrain of patients with Alzheimer’s disease: an in situ hybridization study. Neurosci Lett 1997;221:141-144 Venero JL, Vizuete ML, Revuelta M, Vargas C, Cano J, Machado A. Upregulation of BDNF mRNA and trkB mRNA in the nigrostriatal system and in the lesion site following unilateral transection of the medial forebrain bundle. Exp Neurol 2000;161:3848 Neurotrophic factors in the therapy of Parkinson’s disease 33. Frim DM, Uhler TA, Galpern WR, Beal MF, Breakefield XO, Isacson O. Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 1994;91:5104-5108 34. Volpe BT, Wildmann J, Altar CA. Brainderived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. Neuroscience 1998;83:741-748 35. Levivier M, Przedborski S, Bencsics C, Kang UJ. Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 1995;15:7810-7820 36. Klein RL, Lewis MH, Muzyczka N, Meyer EM. Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer. Brain Res 1999; 847:314320 37. Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay RM. Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci 1994;14:335-347 38. Haque NS, Hlavin ML, Fawcett JW, Dunnett SB. The neurotrophin NT4/5, but not NT3, enhances the efficacy of nigral grafts in a rat model of Parkinson’s disease. Brain Res 1996;712:45-52 39. Engele J, Bohn MC. The neurotrophic effects of fibroblast growth factors on dopaminergic neurons in vitro are mediated by mesencephalic glia. J Neurosci 1991;1:3070-3078 40. Hunot S, Bernard V, Faucheux B et al. Glial cell line-derived neurotrophic factor (GDNF) gene expression in the human brain: a post mortem in situ hybridization study with special reference to Parkinson’s disease. J Neural Transm 1996;103:1043-1052 41. Mogi M, Togari A, Kondo T et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett 1999;270:45-48 42. Kordower JH, Palfi S, Chen EY et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol 1999;46:419-424 43. Mendez I, Dagher A, Hong M et al. Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line-derived neurotrophic factor in patients with Parkinson’s disease. Report of two cases and technical considerations. J Neurosurg 2000;92:863-869 44. Saragovi HU, Gehring K. Development of pharmacological agents for targeting neurotrophins and their receptors. Tr e n d s Pharmacol Sci 2000;21:93-98 45. Nakao N, Yokote H, Nakai K, Itakura T. Promotion of survival and regeneration of nigral dopamine neurons in a rat model of Parkinson’s disease after implantation of embryonal carcinoma-derived neurons genetically engineered to produce glial cell line-derived neurotrophic factor. J Neurosurg 2000;92:659-670 46. Steiner JP, Hamilton GS, Ross DT et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci USA 1997;94:2019-2024 47. Debeir T, Saragovi HU, Cuello AC. A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat. Proc Natl Acad Sci USA. 1999;96:4067-4072 48. Maliartchouk S, Feng Y, Ivanisevic L et al. A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors. Mol Pharmacol 2000;57:385-391 49. Chaiken IM, Williams WV. Identifying struc- FUNCTIONAL NEUROLOGY (16)1 2001 55 F. Facchinetti et al. 50. 51. 52. 53. 54. 56 ture-function relationships in four-helix bundle cytokines: towards de novo mimetics design. Trends Biotechnol 1996;14:369-375 Studer L, Spenger C, Seiler RW, Altar CA, Lindsay RM, Hyman C. Comparison of the effects of the neurotrophins on the morphological structure of dopaminergic neurons in cultures of rat substantia nigra. Eur J Neurosci 1995;7:223-233 Rosenblad C, Kirik D, Devaux B, Moffat B, Phillips HS, Bjorklund A. Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson’s disease after administration into the striatum or the lateral ventricle. Eur J Neurosci 1999;11:1554-1566 Akerud P, Alberch J, Eketjall S, Wagner J, Arenas E. Differential effects of glial cell line-derived neurotrophic factor and neurturin on developing and adult substantia nigra dopaminergic neurons. J Neurochem 1999;73:70-78 Tseng JL, Bruhn SL, Zurn AD, Aebischer P. Neurturin protects dopaminergic neurons following medial forebrain bundle axotomy. Neuroreport 1998;9:1817-1822 Jin BK, Iacovitti L. Dopamine differentiation factors produce partial motor recovery in 6-hydroxydopamine lesioned rats. Neu- FUNCTIONAL NEUROLOGY (16)1 2001 robiol Dis 1995;2:1-12 55. Jin BK, Iacovitti L. Dopamine differentiation factors increase striatal dopaminergic function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice J Neurosci Res 1996;43:331-334 56. Takayama H, Ray J, Raymon HK et al. Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson’s disease. Nat Med 1995;1:53-58 57. No authors listed. A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). Neurology 1999;52:1427-1433 58. No authors listed. A double-blind placebocontrolled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 1996;46:1244-1249 59. Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 1999;107:34s-42s 60. Eriksdotter Jonhagen M, Nordberg A et al. Intracerebroventricular infusion of nerve growth factor in three patients with A l z h e i m e r’s disease. Dementia Geriatr Cogn Disord 1998;9:246-257