Regulation of corticostriatal synaptic plasticity by G protein-coupled receptors.

Dopamine modulation of excitatory neurotransmission is critical in the control of movement, emotion and reward. In the striatum, medium size spiny neurons (MSNs) are responsible for the integration of cortical and thalamic information that flows through parallel, partly overlapping, loops and determines adequate experience-dependent responses. Dopamine acts on MSNs through two sets of G protein-coupled receptors (GPCRs), the D1-like and D2-like receptors, which can have opposing or synergistic downstream effects. Notably, these two types of striatal dopamine receptors are segregated into the striatonigral (direct) and striatopallidal (indirect) projecting neurons. Thus, dopamine receptor expression determines the morphological and functional neuronal phenotype of MSNs. Moreover, dopamine regulates glutamatergic corticostriatal transmission, critically controlling the induction of long-term potentiation and long-term depression at these synapses, regulating striatal synaptic plasticity. In addition to dopamine receptors, the induction and expression of plasticity mechanisms is regulated by other GPCRs, most importantly adenosine A2(A) receptors, metabotropic glutamate mGluR5 receptors and endocannabinoid CB1 receptors. This review focuses on synaptic modulation and plasticity on excitatory corticostriatal synapses by GPCRs.

Stem cells and cell replacement therapy for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder caused by a progressive degeneration of the midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNc) that predominantly affects the ventral population projecting to the dorsal striatum and leads to a gradual dysfunction of the motor system. There is currently no cure for PD. Pharmacological and surgical (e.g. deep brain stimulation) interventions can alleviate some of the symptoms, but lose their efficacy over time. The distinct loss of DA neurons in the SN offers the opportunity to assay neuronal cell replacement, and the clinical transplantation of fetal midbrain neuroblasts in PD patients has shown that this approach is feasible. However, there are multiple problems associated with the use of fetus-derived material, including limited availability. DA neurons derived from stem cells (SC) represent an alternative and unlimited cell source for cell replacement therapies. Currently, human pluripotent SC, such as embryonic (ES), and most recently, induced pluripotent stem cells (iPS), and multipotent (tissue-specific) adult SC are available, although the methodology for a reliable and efficient production of DA neurons necessary for biomedical applications is still underdeveloped. Here, we discuss some essentials for SC and SC-derived DA neurons to become therapeutic agents.

Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates.

The interplay between dopamine and glutamate in the basal ganglia regulates critical aspects of motor learning and behavior. Metabotropic glutamate receptors (mGluR) are increasingly regarded as key modulators of neuroadaptation in these circuits, in normal and disease conditions. Using PET, we demonstrate a significant upregulation of mGluR type 5 in the striatum of MPTP-lesioned, parkinsonian primates, providing the basis for therapeutic exploration of mGluR5 antagonists in Parkinson disease.

[Late nephrology referral influences on morbidity and mortality of hemodialysis patients. A provincial study]. / La referencia tardía al nefrólogo influye en la morbi-mortalidad de los pacientes en hemodiálisis. Un estudio provincial.

OBJECTIVE: To evaluate the influence of late referral to nephrology of the patients with chronic renal failure in the morbimortality of the patients who start hemodialysis. SUBJETS AND METHODS: There were included in the study the patients who started hemodialysis (HD) as first form of treatment, and that survived at least three months in both hospitals of reference of the province of Huesca from january 1990 to december 2001. Patients who started HD after acute renal failure were excluded. Clinical and analytical data were determined for each patient at the start of HD and during the follow-up. Early (ER) and late referral (LR) were defined by the time of first nephrology encounter greather than or less than 4 months respectively, before HD initiation. Morbidity analysis (using multiple linear regression with rate of days of hospitalization as dependent variable) and global and anual during the first three years of follow-up survival analysis (using Cox proportional hazards regression) were carried out. RESULTS: A total of 139 patients (78%) started HD in the ER group and 39 (22%) in LR group. Mean follow-up was similar in both (ER = 34.43 +/- 25.5 months; LR = 34.42 +/- 28.37 months). At the start of dialysis LR was associated to higher proportion of temporary catheters, lower level of hematocrit and albumin, higher comorbidity and higher levels of urea and creatinine. Risk factors selected by the model in the morbidity analysis were index of comorbidity (CI), late referral, serum albumin, urea reduction ratio (URR) and hematocrit (R2 = 0.334, F = 16.97, p < 0.005). The final equation of regression was: Rate of hospitalization's days = 101.12 + (2.45 x CI) - (12. 11 x LR) - (11.57 x Alb.) - (0.43 x PRU) - (0.83 x Hto). Variables selected by Cox's regression model that were associated with survival throughout complete follow-up were hematocrit (RR = -0,207, CI 95% 0.726-0.910, p < 0.0005), index of comorbidity (RR = 0,265, CI 95% 1.066-1.594, p = 0.007), PRU (RR = - 0,059, CI 95% 0.893-0.996, p = 0.038) and type of dialysis membrane (RR = 0,771, Cl 95% 0.260-0.822, p = 0.007). Nevertheless, in successive models fitting after 12, 24 and 36 months of follow-up the variable LR influenced in an independent way survival first two years, losing his significance later. CONCLUSION: In our study patients of the group LR presented a worse clinical and metabolic situation at the beginning of the HD. Later there was demonstrated in this group a higher long-term morbidity and a lower survival the first two years.

Fracaso renal agudo inducido por ácido zoledrónico (zometa) / Zoledronic acid (Zometa)- induced acute renal failure

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La referencia tardía al nefrólogo influye en la morbi-mortalidad de los pacientes en hemodiálisis. Un estudio provincial / Late nephrology referral influences on morbidity and mortality of hemodialysis patients. A provincial study

Objetivo: Evaluar las repercusiones de la referencia tardía al nefrólogo de lospacientes con insuficiencia renal crónica en la morbi-mortalidad de los pacientesque inician hemodiálisis.Pacientes y métodos: Se incluyó en el estudio a los pacientes que iniciaron hemodiálisis(HD) como primera forma de tratamiento, y que sobrevivieron al menosnoventa días, en los dos hospitales de referencia de la provincia de Huesca (HospitalSan Jorge de Huesca y Hospital de Barbastro) en el periodo comprendidoentre el 1-1-1990 y el 31-12-2001. Se excluyeron los pacientes que iniciaron HDcrónica tras presentar fracaso renal agudo. Se recogieron para el estudio variablesclínicas como analíticas tanto al inicio de la HD como durante el seguimiento.Los pacientes se incluyeron en el grupo de referencia precoz (RP) o referenciatardía (RT) dependiendo de si se realizó un seguimiento en la consulta de nefrologíaprevio al inicio de la HD mayor o menor de cuatro meses respectivamente.Se llevó a cabo un análisis de morbilidad mediante la construcción de un modelode regresión lineal múltiple utilizando la tasa de días de ingreso por pacienteañocomo variable dependiente. También se realizó un análisis de supervivenciaglobal y en los tres primeros años de seguimiento mediante el modelo de regresiónde Cox.Resultados: Un total de 139 pacientes (el 78%) iniciaron HD en el grupo de RPy 39 pacientes (el 22%) en el grupo de RT. El seguimiento medio fue similar enambos grupos (RT = 34,43 ± 25,5 meses; RP = 34,42 ± 28,37 meses). Al inicio dela HD la RT se asoció de modo significativo a mayor porcentaje de catéteres temporales,menor nivel de hematocrito y de albúmina, mayor índice de comorbilidady mayores niveles de urea y creatinina. Respecto a la morbilidad el análisis multivariantemostró como factores de riesgo independientes el índice de comorbilidad,la referencia tardía, la albúmina sérica, el porcentaje de reducción de la urea (PRU)y el hematocrito (R2 = 0,334, F = 16,97, p < 0,005). La ecuación de regresión finalfue la siguiente: Tasa de días de ingreso por paciente-año = 101,12 + (2,45 x índicede comorbilidad) – (12,11 x referencia tardía) – (11,57 x Albúmina) – (0,43 xPRU) – (0,83 x Hematocrito). En el análisis de supervivencia global tras el seguimientocompleto el modelo de regresión de Cox seleccionó como variables indeíndicede comorbilidad (RR = 0,265, CI 95% 1,066-1,594, p = 0,007), el PRU (RR= -0,059, CI 95% 0,893-0,996, p = 0,038) y el tipo de membrana del dializador(RR = -0,771, CI 95% 0,260-0,822, p = 0,007). No obstante, tras ajustar sucesivosmodelos al cabo de 12, 24 y 36 meses de seguimiento la variable RP influyó demodo independiente en la supervivencia los dos primeros años, perdiendo su significaciónlos años posteriores.Conclusiones: En nuestro estudio los pacientes del grupo RT presentaron una peorsituación clínica al inicio de la HD. Posteriormente se evidenció en este grupo unamayor morbilidad a largo plazo y una menor supervivencia los dos primeros años

Objetive: To evaluate the influence of late referral to nephrology of the patientswith chronic renal failure in the morbimortality of the patients who start hemodialysis.Subjets and methods: There were included in the study the patients who startedhemodialysis (HD) as first form of treatment, and that survived at least threemonths in both hospitals of reference of the province of Huesca from january1990 to december 2001. Patients who started HD after acute renal failure wereexcluded. Clinical and analytical data were determined for each patient at the startof HD and during the follow-up. Early (ER) and late referral (LR) were defined bythe time of first nephrology encounter greather than or less than 4 months respectively,before HD initiation. Morbidity analysis (using multiple linear regressionwith rate of days of hospitalization as dependent variable) and global and anualduring the first three years of follow-up survival analysis (using Cox proportionalhazards regression) were carried out.Results: A total of 139 patients (78%) started HD in the ER group and 39 (22%)in LR group. Mean follow-up was similar in both (ER = 34.43 ± 25.5 months; LR =34.42 ± 28.37 months). At the start of dialysis LR was associated to higher proportionof temporary catheters, lower level of hematocrit and albumin, higher comorbidityand higher levels of urea and creatinine. Risk factors selected by the modelin the morbidity analysis were index of comorbidity (CI), late referral, serum albumin,urea reduction ratio (URR) and hematocrit (R2 = 0.334, F = 16.97, p < 0.005).The final equation of regression was: Rate of hospitalization's days = 101.12 + (2.45x CI) - (12.11 x LR) - (11.57 x Alb.) - (0.43 x PRU) - (0.83 x Hto). Variables selectedby Cox's regression model that were associated with survival throughout completefollow-up were hematocrit (RR = -0,207, CI 95% 0.726-0.910, p < 0.0005),index of comorbidity (RR = 0,265, CI 95% 1.066-1.594, p = 0.007), PRU (RR = -0,059, CI 95% 0.893-0.996, p = 0.038) and type of dialysis membrane (RR = 0,771,CI 95% 0.260-0.822, p = 0.007). Nevertheless, in successive models fitting after 12,24 and 36 months of follow-up the variable LR influenced in an independent waysurvival first two years, losing his significance later.Conclusion: In our study patients of the group LR presented a worse clinical andmetabolic situation at the beginning of the HD. Later there was demonstrated in thisgroup a higher long-term morbidity and a lower survival the first two years

[Huesca and Teruel survey on hemodialysis management]. / Estudio epidemiológico sobre el tratamiento con hemodiálisis en Huesca y Teruel.

A cross sectional study was performed in order to evaluate the treatment conditions and medical outcomes among 131 prevalent hemodialysis patients (57% males; mean age 66 +/- 12 years) in Huesca and Teruel. Data were collected at 5 hemodialysis units in Huesca and Teruel. Diabetes mellitus, at 30 percent, was the most common cause of renal insufficiency. The mean (+/- SD) urea-reduction ratio (URR) was 66.0 +/- 8.8%. We observed that 56.5% of the population reached an URR higher than 65%. The duration of dialysis session was 220 +/- 24 minutes, with a rate of blood flow 297 +/- 47 ml/min. 36% of patients used high-flux membranes. The patterns of vascular access were: 69% arteriovenous fistula, 5% synthetic graft and 26% catheter. Eighty nine percent of patients were treated with erythropoietin. The mean dose of erythropoietin was 109 +/- 62 UI/Kg weight/week. Thirty nine percent of patients had haemoglobin below 11.0 g/dl (mean 11.2 +/- 1.4 g/dl). Ferritin levels were below 100 ng/ml in 24% of the patients and 25% showed a transferrin saturation index below 20%. Fifty percent of patients were receiving vitamin D. Serum calcium 9.3 +/- 0.8 mg/dl; phosphorous 5.5 +/- 1.5 mg/dl; calcium-phosphorous product 51.5 +/- 14.3 mg/dl; PTHi 433 +/- 459 pg/ml; and aluminium 26.8 +/- 14.5 mcg/l were the mean of main biochemical markers of mineral metabolism. Sixty eight percent of patients had phosphorous levels below 6.0 mg/dl. Thirty seven percent of patients had aluminium levels lower than 20 mcg/l. The mean serum albumin was 3.4 +/- 0.4 g/dl. Forty five percent of patients had albumin below 3.5 g/dl.

Estudio epidemiológico sobre el tratamiento con hemodiálisis en Huesca y Teruel / Huesca and Teruel survey on hemodialysis management

Nos planteamos evaluar el manejo de los pacientes en hemodiálisis (HD) enHuesca y Teruel. Presentamos resultados de 131 pacientes en HD prevalentes enel año 2001. La diabetes mellitus con un 30% fue la causa más frecuente de insuficienciarenal. La media de la dosis de diálisis aplicada, utilizando el porcentajede reducción de urea (PRU), fue 66,0 ± 8,8%. El 56,5% de la población alcanzóun PRU superior a 65%. La duración media de la sesión de HD fue de220 ± 24 minutos, y el flujo sanguíneo de 29,7 ± 47 ml/min. En un 36% de pacientesse emplearon membranas de alta permeabilidad. Los patrones de accesovascular fueron: 69% fístulas arteriovenosas, 5% injerto sintético y 26% catéteres.El 88,5% de la población estaba en tratamiento con eritropoyetina. La dosismedia utilizada fue de 109 ± 62 UI/kg de peso/semana. El 39% de los pacientespresentaba hemoglobina inferior a 11,0 g/dl (media 11,2 ± 1,4 g/dl). Un 24%de los enfermos tenía niveles de ferritina inferiores a 100 ng/ml y un 25% mostrabaíndice de saturación de la transferrina inferior al 20%. Un 50% de pacientesrecibía vitamina D en alguna de sus formas. La media de los principales marcadoresdel metabolismo mineral fue: calcio sérico 9,3 ± 0,8 mg/dl; fósforo 5,5± 1,5 mg/dl; producto calcio-fósforo 51,5 ± 14,3 mg/dl; PTHi 433 ± 459 pg/ml;y aluminio 26,8 ± 14,5 mcg/l. Un 68% de pacientes tenía niveles de fósforo inferiora 6,0 mg/dl y el 37% niveles de aluminio inferior a 20 mcg/l. La albúminasérica media fue 3,4 ± 0,4 g/dl. Un 41% de pacientes presentaba albúmina inferiora 3,5 g/dl

A cross sectional study was performed in order to evaluate the treatment conditionsand medical outcomes among 131 prevalent hemodialysis patients (57%males; mean age 66 ± 12 years) in Huesca and Teruel. Data were collected at 5 hemodialysis units in Huesca and Teruel. Diabetes mellitus, at 30 percent, was themost common cause of renal insufficiency. The mean (± SD) urea-reduction ratio(URR) was 66.0 ± 8.8%. We observed that 56.5% of the population reached anURR higher than 65%. The duration of dialysis session was 220 ± 24 minutes,with a rate of blood flow 297 ± 47 ml/min. 36% of patients used high-flux membranes.The patterns of vascular access were: 69% arteriovenous fistula, 5% synthetycgraft and 26% catheter. Eighty nine percent of patients were treated witherythropoietin. The mean dose of erythropoietin was 109 ± 62 UI/Kg weight/week.Thirty nine percent of patients had haemoglobin below 11.0 g/dl (mean 11.2 ±1.4 g/dl). Ferritin levels were below 100 ng/ml in 24% of the patients and 25%showed a transferrin saturation index below 20%. Fifty percent of patients werereceiving vitamin D. Serum calcium 9.3 ± 0.8 mg/dl; phosphorous 5.5 ± 1.5 mg/dl;calcium-phosphorous product 51.5 ± 14.3 mg/dl; PTHi 433 ± 459 pg/ml; andaluminium 26.8 ± 14.5 mcg/l were the mean of main biochemical markers of mineralmetabolism. Sixty eight percent of patients had phosphorous levels below6.0 mg/dl. Thirty seven percent of patients had aluminium levels lower than 20mcg/l. The mean serum albumin was 3.4 ± 0.4 g/dl. Forty five percent of patientshad albumin below 3.5 g/dl

[Study of immutable variables determining rHuEPO dose requirements on hemodialysis patients]. / Estudio de causas no modificables de pobre respuesta al tratamiento con eritropoyetina en pacientes en hemodiálisis.

Patients receiving recombinant human erythropoietin (rHuEPO) therapy show wide variability in their responsiveness to the drug. Variables that affect rHuEPO dose requirements can be broadly divided into modificable and immutable characteristics. Most of the scientific research on rHuEPO hyporesponsiveness has focused on modificable variables (iron status, dialysis adequacy), while immutable variables such as gender, etiology of chronic renal failure (CRF) and age have been insufficiently explored. A cross sectional study was performed in order to evaluate if immutable patient characteristics determine rHuEPO dose requirements among 215 patients (52% males; mean age 66 +/- 14 years) on hemodialysis (HD) for more than twelve months. Data were collected at 10 hemodialysis units in Aragon. Patients were divided into three groups according to their gender, their cause of CRF (diabetic nephropathy, vascular nephropathy, tubulointerstitial nephropathy and primary glomerulonephritis) and their age (younger than 60 years, from 60 to 75 years, older than 75 years). Despite a similar dose of rHuEPO, women had lower mean hemoglobin (11.1 +/- 1.5 versus 11.6 +/- 1.7 g/dl; p = 0.0258) than men. The greater hemoglobin in men than women may be attributed to greater serum albumin in men (3.5 +/- 0.3 versus 3.7 +/- 0.3 mg/dl; p = 0.0001). Requirements of rHuEPO were higher in the patients with etiology of primary glomerulonephritis compared with those with the other etiologies, even those with diabetic nephropathy (p = 0.0374). The rHuE-PO doses required to obtain similar hemoglobin levels were higher in patients younger than 60 years (p = 0.0249). We conclude that women, patients with primary glomerulonephritis as cause of CRF, and patients younger than 60 years showed the highest requirements of rHuEPO doses.

Terapia celular en enfermedades neurodegenerativas: perspectiva desde el modelo experimental de enfermedad de Parkinson / Cellular therapy in neurodegenerative diseases: perspective from the experimental model of Parkinson's disease

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Functional imaging of the dopamine system: in vivo evaluation of dopamine deficiency and restoration.

Dopamine deficiency causes a severe impairment in motor function in patients with Parkinson's disease (PD) and in experimental animal models. Recent developments in neuroimaging techniques provide a means to assess in vivo the state of the dopamine system. From a functional perspective, four levels need to be operative and integrated in the system: the dopamine cell (pre-synaptic), the striatal dopamine receptors (post-synaptic), adequate release of dopamine (intra-synaptic), and the cortico-subcortical motor projections. Neuroimaging functional methods can be used to estimate, at these four levels, dopamine cell degeneration, adaptive responses to injury and, importantly, the effect of therapeutic interventions. In this respect, data from functional imaging studies at clinical and pre-clinical stages, support the idea that cell replacement therapy might achieve a more physiological restoration of the dopamine motor system than other therapies (such as ablative surgery, administration of precursor, deep brain stimulation) that currently are equally or more effective in relieving motor symptoms.

Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats.

In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment.

In vitro generation and transplantation of precursor-derived human dopamine neurons.

The use of in vitro expanded human CNS precursors has the potential to overcome some of the ethical, logistic and technical problems of fetal tissue transplantation in Parkinson disease. Cultured rat mesencephalic precursors proliferate in response to bFGF and upon mitogen withdrawal, differentiate into functional dopamine neurons that alleviate motor symptoms in Parkinsonian rats (Studer et al. [1998] Nat. Neurosci. 1:290-295). The successful clinical application of CNS precursor technology in Parkinson disease will depend on the efficient in vitro generation of human dopaminergic neurons. We demonstrate that human dopamine neurons can be generated from both midbrain and cortical precursors. Transplantation of midbrain precursor-derived dopamine neurons into Parkinsonian rats resulted in grafts rich in tyrosine hydroxylase positive neurons 6 weeks after transplantation. No surviving tyrosine hydroxylase positive neurons could be detected when dopamine neurons derived from cortical precursors were grafted. Our data demonstrate in vitro derivation of human dopamine neurons from expanded CNS precursors and encourage further studies that systematically address in vivo function and clinical potential.

[Disorders in gaze saccades in Huntington disease. Clinical correlations]. / Störung der Blicksakkaden bei der Huntington-Krankheit. Klinische Korrelationen.

Oculomotor abnormalities have long been recognized in Huntington's disease (HD). The precise correlation between them and other clinical findings has not yet been determined. Using videonystagmography, we studied reflexive, visually guided horizontal saccades in 32 patients with genetically confirmed HD: nine female and 23 male patients, including six with young onset HD (YOHD), 19 with adult onset HD (AOD), and seven with late onset HD (LOHD). Huntington's patients exhibited increased saccade latency (P < 0.05), decreased saccade velocity (P < 0.0005), and impaired saccade accuracy (P < 0.01). A significant difference between the different groups of patients could be determined, and YOHD was characterized by normal latency and decreased saccade velocity while LOHD showed increased saccade latency but normal velocity. Furthermore, we found a significant difference between the genetic data (length of CAG-repeats) and saccadic abnormalities, with higher repeat numbers corresponding to shorter latency and decreased velocity, as in YOHD. The study of saccade parameters might be useful as an objective method for testing the effectiveness of future therapies.

Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain.

Adeno-associated virus type2 (AAV-2) binds to heparan-sulfate proteoglycans on the cell surface. In vivo, attachment of viral particles to cells adjacent to the injection tract limits the distribution of AAV-2 when infused into the CNS parenchyma and heparin co-infusion might decrease the binding of AAV-2 particles to cells in the vicinity of the infusion tract. We have previously shown that heparin co-infusion combined with convection enhanced delivery enhances distribution of the GDNF family trophic factors (heparin-binding proteins) in the rat brain. In this work we show that heparin co-infusion significantly increases the volume of distribution of AAV-2 as demonstrated by immunoreactivity to the transgene product 6 days after infusion into the rat striatum.

Heparin coinfusion during convection-enhanced delivery (CED) increases the distribution of the glial-derived neurotrophic factor (GDNF) ligand family in rat striatum and enhances the pharmacological activity of neurturin.

Convection-enhanced delivery (CED) distributes macromolecules in the brain in a homogeneous, targeted fashion in clinically useful volumes. However, the binding of growth factors to heparin-binding sites in the extracellular matrix may limit the volume of distribution (V(d)). To overcome this limitation, we examined the effects of heparin coinfusion on V(d) of glial-derived neurotrophic factor (GDNF), neurturin (NTN), artemin, and a nonspecifically bound protein, albumin. Heparin coinfusion significantly enhanced the V(d) of GDNF and GDNF-homologous trophic factors, probably by binding and blocking heparin-binding sites in the extracellular matrix. Furthermore, coinfusion of heparin with NTN enhanced striatal dopamine metabolism, compared to trophic factor administered alone. The negligible benefit of GDNF in recent clinical trials of Parkinson's disease may result from limited tissue distribution. Heparin coinfusion during CED targeting the striatum may alleviate this important limitation. This study demonstrates the influence of receptor binding on the distribution of trophic factors in the CNS.