The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys

doi:10.1016/S0967-5868(97)90076-X

Journal of Clinical Neuroscience

Volume 4, Issue 2, April 1997, Pages 218-227

https://doi.org/10.1016/S0967-5868(97)90076-X Get rights and content

Abstract

This study was designed to further investigate the role of the subthalamic nucleus (STN) and globus pallidus internus (GPi) in the pathophysiology of Parkinson's disease. The prevailing theory about the pathophysiology of Parkinson's disease (PD) predicts that there is overactivity of the subthalamo-pallidal pathway. In order to inactivate that pathway, naive and hemiparkinsonian monkeys were locally administered either muscimol (to reversibly inactivate the contralateral STN) or kynurenic acid (to reduce glutamatergic activity in the contralateral GPi). Three naive and 2 hemiparkinsonian monkeys were studied. Intra-carotid MPTP was administered to produce 2 hemiparkinsonian monkeys. Injection sites of muscimol and kynurenic acid in the brain were confirmed electrophysiologically and histologically. Injections of muscimol into the STN in naive and hemiparkinsonian monkeys caused reversible contralateral dystonia, but did not alleviate Parkinsonism. Only one kynurenic acid injection into GPi partially alleviated Parkinsonism. On the basis of the results in this study, aspects of the currently accepted hypothesis of the pathophysiology of PD cannot be confirmed. However, this study reports that the STN has an important role in the production of dystonia. This experimental model of dystonia will prove suitable for further study of both the mechanisms causing dystonia as well as for possible therapeutic approaches to its treatment.

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Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease
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Citation Excerpt :
This was demonstrated by attenuation of MPP+-induced cell death by pre-treatment with KYNA in human dopaminergic neuronal cell lines (Lee do et al., 2008). Moreover, administration of KYNA directly into the globus pallidus internus of Parkinsonian non-primate protected against MPTP-induced toxicity (Butler et al., 1997; Graham et al., 1990). In addition, systemic administration of exogenous KYNA has very limited therapeutic efficacy because KYNA has poor permeability across the BBB and a very short biological half-life.
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Neuroinflammation leads to microglia activation and release of a large number of proinflammatory mediators. The kynurenine pathway (KP) of tryptophan catabolism is one of the major regulators of the immune response and is also likely to be implicated in the inflammatory and neurotoxic events in Parkinsonism. Several neuroactive compounds are produced through the KP that can be either a neurotoxic, neuroprotective or immunomodulator. Among these metabolites kynurenic acid (KYNA), produced by astrocytes, is considered as neuroprotective whereas quinolinic acid (QUIN), released by activated microglia, can activate the N-methyl-d-aspartate (NMDA) receptor-signalling pathway, leading to excitotoxicity and amplify the inflammatory response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that some of the KP metabolites could be used as prognostic biomarkers and that pharmacological modulators of the KP enzymes could represent a new therapeutic strategy for PD.
Postural changes after lesions of the substantia nigra pars reticulata in hemiparkinsonian monkeys
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Current neurosurgical strategies target overactive brain regions including the subthalamic nucleus, globus pallidus and thalamus to control various symptoms of Parkinson's disease. Subthalamotomy improves akinesia and can induce postural deficits in both parkinsonian humans and animals, pallidotomy improves limb dyskinesia and more variably, distal bradykinesia whilst thalamotomy improves tremor. Because the SNr also becomes overactive in PD and there are few surgical studies in parkinsonian primates, we therefore evaluated the effects of lesioning the SNr in hemiparkinsonian marmosets to establish the effects on symptomatology. Nine monkeys received unilateral 6-hydroxydopamine (6-OHDA) lesions. Seven weeks later, four received kainic acid lesions of the SNr. Behavioural tests were performed prior to 6-OHDA surgery and then fortnightly for 14 weeks. Unilateral 6-OHDA lesions induced ipsilateral postural bias, ipsilateral rotation after amphetamine injection and bradykinesia. Whilst, SNr lesions significantly altered the direction of head position and amphetamine-induced rotation relative to 6-OHDA lesions, there was no improvement in 6-OHDA-induced reaching deficits or sensorimotor neglect. Unbiased quantitation of the nigral lesions showed on average 88% loss of dopaminergic neurons after 6-OHDA lesions and 77% loss of non-dopaminergic neurons after SNr lesions. Our results demonstrate that the SNr is important in body orientation changes in parkinsonism.
Convulsive and postural effects of lesioning the mid-substantia nigra pars reticulata in naïve and 6-hydroxydopamine lesioned rats
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The subthalamic nucleus is targeted for the treatment of Parkinson’s disease. Unilateral lesions improve some aspects of parkinsonism but produce postural abnormalities in animal models but the exact pathways producing these effects remain to be defined. Using a battery of tests we evaluated the effects of lesioning one of the two major subthalamic targets, the substantia nigra pars reticulata in naı̈ve and 6-OHDA lesioned rats. Lesions targeting the mid-substantia nigra pars reticulata resulted in acute tonic–clonic seizures and intense contralateral rotational asymmetry. During the first month after substantia nigra pars reticulata lesions there was normalisation of the ipsilateral head position bias induced by unilateral 6-OHDA lesions, significant contralateral body axis bias but no significant alteration of apomorphine induced rotation and sensorimotor neglect in 6-OHDA lesioned rats. Combined with our previous data, this suggests that subthalamic projections via the substantia nigra pars reticulata are important in seizures and postural behaviours. Therefore unilateral subthalamotomy probably induces postural deficits in hemiparkinsonian animals via projections involving the substantia nigra pars reticulata. This has implications for patients undergoing subthalamotomy for treatment of Parkinson’s disease.
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Expression of nitric oxide synthase (NOS) mRNA in post mortem brain was studied in putamen, globus pallidus and subthalamic nucleus (STN) of neurologically normal control subjects and patients with Parkinson's disease (PD) using in situ hybridization histochemistry. In PD, a significant increase in NOS mRNA expression was observed in the dorsal two-thirds of the STN with respect to the ventral one-third of the STN. A significant increase in NOS mRNA expression per cell in the medial medullary lamina of the globus pallidus was also observed in PD. NOS mRNA expression was significantly reduced in PD putamen. These findings provide evidence of increased activity of STN neurotransmitter systems in PD and demonstrate for the first time in any species that basal ganglia nitric oxide systems can be selectively regulated in response to changes in dopaminergic input.
Targeting the subthalamic nucleus in the treatment of Parkinson's disease
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As more is learnt about the functional implications of basal ganglia connectivity, the role of the subthalamic nucleus as a target site for stereotactic procedures in the amelioration of the symptoms of Parkinson’s disease is becoming clearer. A comparison of various neurosurgical procedures in the disease is discussed in relation to current thinking about circuitry. Experimental investigations involving lesioning or stimulation of the subthalamic nucleus in nonhuman primate models and in clinical studies of Parkinson’s disease are compared. Neurosurgical procedures that lesion structures bilaterally are more likely to induce side effects than is deep-brain stimulation, which has the added advantage of reversibility and which is more amenable to titration in relation to medication and dosage. A small but growing number of parkinsonian patients have received subthalamic stimulation either unilaterally or bilaterally. Stimulation of the subthalamic nucleus ameliorates tremor, rigidity and hypokinesia, as opposed to thalamic stimulation which is probably best reserved for tremor-dominant patients. Such procedures also do not involve the same complex technical and ethical issues that are associated with foetal mesencephalic grafting. Although subthalamic stimulation shows great promise, it has not been developed to the point where it can be used as more than an experimental treatment. Further experimental research is required before the new strategies can be used on a larger scale.
Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson’s Disease—A Narrative Review
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Laboratory studyThe effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys

Abstract

Brain Res

Tins

Brain Res

Life Sci

Life Sci

Neuroscience

Neurosci Lett

Exp Neurol

Brain Res

Exp Neurol

Brain Res

Neuroscience

Brain Res

Neuroscience

Brain Res

Brain Res

Brain Res

Experimental hemiballismus in the baboon produced by injection of a gamma-aminobutyric acid antagonist into the basal ganglia

Neurosci Lett

Experimental hemichorea/hemiballismus in the monkey

Excitotoxic acid lesions of the primate subthalamic nucleus result in transient dyskinesias of the contralateral limbs

J Neurophysiol

Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey

Exp Brain Res

Altered tonic activity of neurons in the globus pallidus and subthalamic nucleus in the primate MPTP model of parkinsonism

The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism

J Neurophysiol

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

Science

Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate

Mov Dis

Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys

Eur J Neurosci

Delivery of muscimol to the subthalamic nucleus or kynurenic acid to the globus pallidus of hemiparkinsonian monkeys

Soc Neuro Abs

Activity of pallidal neurons during movement

J Neurophysiol

Primate globus pallidus and subthalamic nucleus: functional organization

J Neurophysiol

The monkey globus pallidus: neural discharge properties in relation to movement

J Physiol (Lond)

Sensory characteristics of monkey thalamic and motor cortex neurone

J Physiol

Neural activity in the monkey anterior ventrolateral thalamus during trained, ballistic movements

J Neurophysiol

Physiologic properties and somatotopic organization of the primate motor thalamus

J Neurophysiol

Laboratory study
The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys