Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson’s disease

Jg, de Yébenes; Fahn, Stanley; Jackson-Lewis,; Jorge, Pablo; Ma, Mena; Reiriz, Julia

doi:10.1007/978-3-7091-8954-2_13

Cited by 8 publications

(7 citation statements)

References 22 publications

(9 reference statements)

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“…Second, microglia-derived factors were detected only after the occurrence of substantial neuronal damage. Third, consistent with other reports (37)(38)(39), pargyline completely blocked the damage of dopaminergic neurons induced by MPTP. More importantly, associated with the attenuation of MPTP neurotoxicity, pargyline abolished the microglial activation (this study).…”

Section: Discussionsupporting

confidence: 92%

Critical role of microglial NADPH oxidase‐derived free radicals in the in vitro MPTP model of Parkinson's disease

et al. 2003

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1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons as seen in Parkinson's disease. Although increasing evidence suggests an involvement of glia in MPTP neurotoxicity, the nature of this involvement remains unclear. Exploiting the advantage of cell culture systems, we demonstrated that microglia, but not astroglia, significantly enhanced the progression of MPTP-induced dopaminergic neurodegeneration. Characterization of the temporal relationship between neurodegeneration and microglial activation demonstrates that reactive microgliosis resulting from MPTP-initiated neuronal injury, but not direct activation, underlies the microglia-enhanced MPTP neurotoxicity. Mechanistically, through the release of NADPH oxidase-derived reactive oxygen species, microglia contribute to the progressive neuronal damage. Among the factors measured, the production of extracellular superoxide was the most prominent. NADPH oxidase inhibitor, apocynin, attenuated MPTP-induced dopaminergic neurodegeneration only in the presence of glia. More importantly, dopaminergic neurons from mice lacking NADPH oxidase, a key enzyme for superoxide production in immune cells, are significantly more resistant to MPTP neurotoxicity than those from wild-type controls, and microglia dictate the resistance. This study demonstrates that reactive microgliosis triggered by MPTP-induced neuronal injury and NADPH oxidase-mediated superoxide production in microglia constitute an integral component of MPTP neurotoxicity. This study also suggests that NADPH oxidase may be a promising target for therapeutic interventions in Parkinson's disease.

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Section: Discussionsupporting

confidence: 92%

Critical role of microglial NADPH oxidase‐derived free radicals in the in vitro MPTP model of Parkinson's disease

et al. 2003

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“…Local infusion has also been used in treatment for models of other neurological disorders. Intraventricular infusion of dopamine agonists has been used in animal models of Parkinson's syndrome (8). Dexamethasone has been delivered focally by osmotic pump to regions of brain tumors in rabbits (9).…”

Section: Discussionmentioning

confidence: 99%

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

1997

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Summary: Purpose:We evaluated the efficacy of local perfusion of diazepam (DZP) in suppression of EEG spikes and behavioral seizures produced by bicuculline methiodide (BMI) applied to rat sensory motor cortex and hippocampus.Methods: Data were obtained from 37 rats implanted with EEG head plugs and perfusion cannulas. BMI 4 mM, 5 pl was infused on neocortex through the epidural space in 23 rats. BMI 0.1 mM, 2 p1 was infused into the left hippocampus in 14 rats.Results: DZP 0.75-1.0 mg markedly reduced the spiking to a level of 9.9 t 15.8% of baseline for DZP as compared with 90.2 t 57.9% of baseline for vehicle-treated rats. DZP reduced spiking in a hippocampal BMI focus to 1.9 k 2.4% of baseline spiking, as compared with 98.0 & 95.6% of that in vehicle-treated animals. The amount of spread of solution was estimated with methylene blue (MB) injections. Ictal events also were attenuated. In most of the animals, systemic levels of DZP were unmeasurable and injection on the contralateral side did not reduce spiking.Conclusions: These findings suggest that focal application of antiepileptic drugs (AEDs) in brain may be a useful new avenue for therapy of intractable partial seizures. Key Words: Seizures-Epilepsy-Electrophysiology-DiazePam-Bicuculline-Drug delivery systems.The mainstay of therapy for epilepsy remains systemic administration of antiepileptic drugs (AEDs). Approximately 25-30% of people with epilepsy are unresponsive to or intolerant of systemic medications (1). Some of these patients can be helped by surgical removal of the seizure focus (2), most commonly an anterior mesial temporal seizure lobe focus. Nevertheless, some individuals with intractable partial (focal) seizures in critical areas of the brain or in more than one location are not candidates for surgery. These patients experience ongoing partial or secondarily generalized seizures. New methods of treating such patients are required.We used white rats to study the local perfusion of diazepam (DZP) directly on brain tissue to stop focal seizures. These studies in an animal model system can serve as a first step toward examining the feasibility of a local perfusion system for epilepsy in humans. Preliminary reports of our findings were published in abstract form (3). METHODSRandomized, double-blinded data were obtained from 37 male Sprague-Dawley white rats weighing 250-500 g obtained from the Charles River breeding colony. In the first stage of the experiment, bone screws and cannulas were implanted in the rats. Each rat was anesthetized with ketamine 40 mg/kg, xylazine 5.5 mg/kg, and acepromazine maleate 0.8 mg/kg by intramuscular injection in -0.2-ml vol.While under anesthesia, rats were placed in a head holder with atraumatic ear bars, and the cranium was exposed through a longitudinal incision. Bone screws (Small Parts, Coral Gables, FL, U.S.A.) were implanted in the left and right frontal bones and the middle and posterior left and right parietal bones and overlying the midline sinus as a reference. A wire was inserted in neck muscle as...

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“…All animals treated with reserpine exhibited behavioral features associated with an acute loss of dopamine. Although striatal dopamine depletion was not measured in the present study, previous studies have reported that reserpine treatment reduces dopamine levels to 5% of that of nonreserpinised animals 47, 48. Reserpine treatment causes a reversible depletion of vesicular dopamine and does not result in actual loss of dopaminergic neurons; this mechanism makes it a useful acute model for studying the effects of acute dopamine depletion and the regulation of receptors in the basal ganglia circuit by dopamine.…”

Section: Discussionmentioning

confidence: 59%

Striatal delta opioid receptor binding in experimental models of Parkinson's disease and dyskinesia

Hallett

Brotchie

2007

Movement Disorders

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Enhanced delta opioid receptor transmission may represent an endogenous compensatory mechanism in parkinsonism to reduce the activity of the indirect striatopallidal pathway following dopamine depletion. Furthermore, increased delta opioid receptor transmission may be causative in the production of dyskinesia following repeated dopaminergic treatment in Parkinson's disease. The present study employed radioligand receptor autoradiography, using [3H]naltrindole, a ligand selective for the delta opioid receptor, to assess delta opioid receptor binding sites in forebrain regions of reserpine-treated rats, and in parkinsonian nondyskinetic, and dyskinetic MPTP-lesioned macaques. In reserpine-treated animals, specific delta opioid binding was increased in premotor cortex (+30%), sensorimotor striatum (+20%), and associative striatum (+17%) rostrally, but was not changed in caudal forebrain. In contrast, delta opioid receptor binding was not significantly altered at any region analyzed, in either nondyskinetic or dyskinetic, MPTP-lesioned macaques, compared to normal. These results suggest that transient changes in delta opioid receptor binding may occur in motor circuits following acute dopamine depletion. However, in the more chronic MPTP-lesioned macaque model, simple changes in delta opioid receptor number or affinity are unlikely to contribute to mechanisms for abnormal opioid transmission in Parkinson's disease and dyskinesia.

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Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson’s disease

Cited by 8 publications

References 22 publications

Critical role of microglial NADPH oxidase‐derived free radicals in the in vitro MPTP model of Parkinson's disease

Critical role of microglial NADPH oxidase‐derived free radicals in the in vitro MPTP model of Parkinson's disease

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

Striatal delta opioid receptor binding in experimental models of Parkinson's disease and dyskinesia

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