Executive dysfunction and cognitive decline, a non-motor symptom of Parkinson's disease captured in animal models.

The non-motor symptoms of Parkinson's disease (PD) have gained increasing attention in recent years due to their significant impact on patients' quality of life. Among these non-motor symptoms, cognitive dysfunction has emerged as an area of particular interest where the clinical aspects are covered in Chapter 2 of this volume. This chapter explores the rationale for investigating the underlying neurobiology of cognitive dysfunction by utilising translational animal models of PD, from rodents to non-human primates.

The selective 5-HT receptor agonist NLX-112 displays anxiolytic-like activity in mice.

Anxiety is amongst the commonest neuropsychiatric disorders, and there is a large body of evidence to suggest that abnormalities in serotonergic function are involved in its pathogenesis. Several studies have implicated 5-HT receptor activation in mitigating anxiety disorders, so this study investigated the acute effects of a highly selective, potent and efficacious 5-HT receptor full agonist, NLX-112 (a.k.

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate.

The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets.

Contractile dysfunction and nitrergic dysregulation in small intestine of a primate model of Parkinson's disease.

Bowel dysfunction is a common non-motor symptom in Parkinson's disease (PD). The main contractile neurotransmitter in the GI tract is acetylcholine (ACh), while nitric oxide (NO) causes the relaxation of smooth muscle in addition to modulating ACh release. The aim of this study was to characterise functional and neurochemical changes in the isolated ileum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset, an established model of PD motor dysfunction.

Magnetic resonance imaging and tensor-based morphometry in the MPTP non-human primate model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder producing a variety of motor and cognitive deficits with the causes remaining largely unknown. The gradual loss of the nigrostriatal pathway is currently considered the pivotal pathological event. To better understand the progression of PD and improve treatment management, defining the disease on a structural basis and expanding brain analysis to extra-nigral structures is indispensable.

Altered detrusor contractility in MPTP-treated common marmosets with bladder hyperreflexia.

Bladder hyperreflexia is a common non-motor feature of Parkinson's disease. We now report on the contractility of the isolated primate detrusor strips devoid of nerve input and show that following MPTP, the amplitude and frequency of spontaneous contraction was increased. These responses were unaffected by dopamine D1 and D2 receptor agonists A77636 and ropinirole respectively.

The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats.

The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets.

Loss of locus coeruleus noradrenergic neurons alters the inflammatory response to LPS in substantia nigra but does not affect nigral cell loss.

In Parkinson's disease (PD), destruction of noradrenergic neurons in the locus coeruleus (LC) may precede damage to nigral cells and subsequently exaggerate dopaminergic cell loss. We examine if destruction of the locus coeruleus with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) alters dopaminergic cell loss in substantia nigra (SN) initiated by lipopolysaccharide (LPS) in the rat through an effect on glial cell activation. In rats, a single intraperitoneal dose of DSP-4 administered 8 days previously, caused a marked loss of tyrosine hydroxylase positive neurons in LC but no change in dopaminergic cell number in SN.

Lipopolysaccharide-induced nigral inflammation leads to increased IL-1β tissue content and expression of astrocytic glial cell line-derived neurotrophic factor.

Reactive gliosis and inflammatory change is a key component of nigral dopaminergic cell death in Parkinson's disease (PD). Astrocyte derived glial cell line-derived neurotrophic factor (GDNF) promotes the survival and growth of dopaminergic neurones and it protects against or reverses nigral degeneration induced by 6-OHDA and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rodents and primates. But the effect of increased levels of pro-inflammatory cytokines on the release of GDNF is unknown.

Mechanisms underlying the onset and expression of levodopa-induced dyskinesia and their pharmacological manipulation.

A significant proportion of patients with Parkinson's disease (PD) receiving dopamine replacement therapy in the form of levodopa develop dyskinesia that becomes a major complicating factor in treatment. Dyskinesia can only be effectively treated by a reduction in drug dose, which limits efficacy, by co-administration of the weak NMDA antagonist amantadine or by surgical treatment (pallidotomy, DBS). This raises the important question of why dyskinesia occurs in PD and how it can be avoided or suppressed by pharmacological treatment.

The effect of nNOS inhibitors on toxin-induced cell death in dopaminergic cell lines depends on the extent of enzyme expression.

Nitric oxide is linked with neurodegeneration in Parkinson's disease (PD) through the involvement of both inducible (iNOS) and neuronal nitric oxide synthase (nNOS). While non-selective NOS inhibitors are neuroprotective, the role of nNOS has not been determined using selective NOS inhibitors. The present study investigated the neuroprotective effect of selective iNOS and nNOS inhibitors on MPP(+)- and MG-132-induced cell death in cell lines with differing levels of nNOS expression.

Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia.

Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets.

An immunohistochemical and stereological analysis of PSI-induced nigral neuronal degeneration in the rat.

Systemic administration of the proteasomal inhibitor I (PSI) to rats was reported to cause progressive nigral dopaminergic neuronal loss but this is disputed. A major controversy centres over the use of manual counting of tyrosine hydroxylase (TH) positive neurons at the level of third cranial nerve as opposed to employing systematic stereological analysis of cell loss in the entire substantia nigra (SN). To provide a method of marking SN neurones independent of protein expression, fluorogold (FG) was stereotaxically injected bilaterally into the striatum of male Wistar rats to retrogradely label nigral dopaminergic neurons.

Continuous subcutaneous infusion of pramipexole protects against lipopolysaccharide-induced dopaminergic cell death without affecting the inflammatory response.

The D2/D3 dopamine receptor agonist pramipexole, protects against toxin-induced dopaminergic neuronal destruction but its mechanism of action is unknown. Inflammation following glial cell activation contributes to cell death in Parkinson's disease and we now report on the effects of acute or chronic administration of pramipexole on lipopolysaccharide (LPS) induced inflammation and nigral dopaminergic cell death in the rat. At 48 h and 30 days following supranigral administration of LPS, approximately 70% of tyrosine hydroxylase (TH) immunoreactive (-ir) cells in substantia nigra had degenerated with a corresponding loss of TH-ir terminals in the striatum.

Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems.

Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the alpha-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer's, in comparison to control and this reduction correlated with both the severity and duration of dementia.

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\ increased motor disability.

5-Hydroxytryptamine 1a (5-HT(1a)) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT(1a) receptors and also possess dopamine antagonist actions. We now report on the effects of (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-(+)-8-OHDPAT], a selective 5-HT(1a) agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets.

Pramipexole protects against MPTP toxicity in non-human primates.

The neurotoxin MPTP induces nigral dopaminergic cell death in primates and produces a partial model of Parkinson's disease (PD). Pramipexole is a D2/D3 dopamine receptor agonist used in the symptomatic treatment of PD, and which also protects neuronal cells against dopaminergic toxins in vitro. We now demonstrate that pramipexole partially prevents MPTP toxicity in vivo in a primate species.

Unilateral pallidotomy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets exhibiting levodopa-induced dyskinesia.

Pallidotomy paradoxically reduces the intensity of levodopa-induced dyskinesia without worsening motor symptoms. The reasons for this are not clear and no experimental study has investigated this phenomenon. The objective of this investigation was to evaluate the effects of unilateral pallidotomy on locomotor activity, motor disability and levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated levodopa-primed common marmosets.

Age-associated changes in protein oxidation and proteasome activities in rat brain: modulation by antioxidants.

The free radical theory of ageing postulates that age-associated neurodegeneration is caused by an imbalance between pro-oxidants and antioxidants resulting in oxidative stress. The current study showed regional variation in brain susceptibility to age-associated oxidative stress as shown by increased lipofuscin deposition and protein carbonyl levels in male rats of age 15-16 months compared to control ones (3-5 months). The hippocampus is the area most vulnerable to change compared to the cortex and cerebellum.

The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation.

Sustained reactive microgliosis may contribute to the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease (PD), in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed human and in non-human primates. However, the temporal relationship between glial cell activation and nigral cell death is relatively unexplored. Consequently, the effects of acute (24 h) and chronic (30 days) glial cell activation induced by unilateral supranigral lipopolysaccharide (LPS) administration were studied in rats.

A modified MPTP treatment regime produces reproducible partial nigrostriatal lesions in common marmosets.

Standard MPTP treatment regimens in primates result in > 85% destruction of nigral dopaminergic neurons and the onset of marked motor deficits that respond to known symptomatic treatments for Parkinson's disease (PD). The extent of nigral degeneration reflects the late stages of PD rather than events occurring at its onset. We report on a modified MPTP treatment regimen that causes nigral dopaminergic degeneration in common marmosets equivalent to that occurring at the time of initiation of motor symptoms in man.

Role of inducible nitric oxide synthase in N-methyl-d-aspartic acid-induced strio-nigral degeneration.

N-Methyl-d-aspartate (NMDA)-induced striatal excitotoxicity is mediated by nitric oxide (NO) but the role of inflammatory mechanisms and inducible nitric oxide synthase (iNOS) induction is not clear. Unilateral intrastriatal administration of NMDA to rats resulted in the loss of intrinsic striatal neurones and the degeneration of NADPH-diaphorase positive interneurones within 24 h. NMDA administration caused activation of glial fibrillary acidic protein positive astroglial cells and MAC-1 ir microglia.

3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.

Ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] was shown to prolong the action of L-3,4-dihydroxyphenylalanine (L-DOPA) while suppressing dyskinesia in a single patient with Parkinson's disease (PD). The clinical basis of this effect of MDMA is unknown but may relate to its actions on either dopaminergic or serotoninergic systems in brain. In normal, drug-naive common marmosets, MDMA administration suppressed motor activity and exploratory behavior.