Degeneration Of Substantia Nigra Pars Compacta Research Articles

5 Midbrain Degeneration and Cognition in Parkinson’s Disease

Objective:Neuromelanin imaging is an emerging biomarker for PD as it captures degeneration of the midbrain, a process which is associated with the motor symptoms of the disease. Currently, it is unknown whether this degeneration also contributes to cognitive dysfunction in PD beyond dysfunction associated with fronto-subcortical systems, as quantitative examination of substantia nigra (SN) degeneration could not be studied until recently.In the current study, we examine whether neuromelanin signal is associated with broader cognitive dysfunction in PD patients with varying degrees of cognitive impairment: PD with normal cognition (PD-NC), PD with mild cognitive impairment (PD-MCI), and healthy controls (HC).Participants and Methods:11 PD-NC, 16 PD-MCI and 14 age and sex-matched healthy controls (HC) participated in the study. PD participants were diagnosed with MCI based on the Movement Disorders Society Task force, Level II assessment (comprehensive assessment). In addition, all participants underwent an MRI scan that included a T1-weighted sequence and a neuromelanin-sensitive (NM-MRI) sequence. Contrast-to-noise-ratio of the substantia nigra pars compacta (SNc) was calculated and a distribution-corrected z-score was used to identify the number of extrema voxels for each individual, suggestive of the number of voxels that have exhibited significant degeneration (extrema_count). An analysis of covariance (ANCOVA) was used to evaluate group differences between HC, PD-NC, and PD-MCI in the extrema_count accounting for age, sex, and education. A multiple regression for each cognitive variable with extrema_count as the dependent variable adjusting for age, sex, and education were conducted.Results:A significant main effect of group (F(2, 33) = 33.548 ; p < 0.001) indicated that PD-NC (21.55 ± 12.57) and PD-MCI (43.64 ± 32.84) patients exhibited significantly greater extrema_counts relative to HC (3.36 ± 3.61; both p < 0.001). Regression results indicated that higher extrema_counts were associated with worse cognitive performance across cognitive domains, including working memory (Digit Span Backward; R2 = .357, F(1,20) = 5.295, p = .032), (Hopkins Verbal Learning Test - Revised, Trials 1 to 3; R2 = .432, F(1,20) = 5.819, p = .026).Conclusions:PD patients (PD-NC and PD-MCI) exhibited decreased neuromelanin in the SNc relative to healthy controls, confirming the ability of the NM-MRI sequence to differentiate PD from HC. There was no significant difference in SNc neuromelanin levels between PD-NC patients and PD-MCI patients, however, this is likely due to the small sample size. In addition, significant SNc degeneration was associated with worse cognitive performances in tasks associated with working memory and executive functioning. These results warrant further examination of the role of SN in PD patients with differing levels of cognitive impairment.

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice.

Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration.

Differential vulnerability of locus coeruleus and dorsal raphe neurons to chronic methamphetamine-induced degeneration.

Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in axons of substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) dopamine neurons. Chronic administration of meth results in SNc degeneration and MAO inhibition is neuroprotective, whereas, the VTA is resistant to degeneration. This differential vulnerability is attributed, at least in part, to the presence of L-type Ca2+ channel-dependent mitochondrial stress in SNc but not VTA dopamine neurons. MAO is also expressed in other monoaminergic neurons such as noradrenergic locus coeruleus (LC) and serotonergic dorsal raphe (DR) neurons. The impact of meth on mitochondrial stress in LC and DR neurons is unknown. In the current study we used a genetically encoded redox biosensor to investigate meth-induced MAO-dependent mitochondrial stress in LC and DR neurons. Similar to SNc and VTA neurons, meth increased MAO-dependent mitochondrial stress in axonal but not somatic compartments of LC norepinephrine and DR serotonin neurons. Chronic meth administration (5 mg/kg; 28-day) resulted in degeneration of LC neurons and MAO inhibition was neuroprotective whereas DR neurons were resistant to degeneration. Activating L-type Ca2+ channels increased mitochondrial stress in LC but not DR axons and inhibiting L-type Ca2+ channels in vivo with isradipine prevented meth-induced LC degeneration. These data suggest that similar to recent findings in SNc and VTA dopamine neurons, the differential vulnerability between LC and DR neurons can be attributed to the presence of L-type Ca2+ channel-dependent mitochondrial stress. Taken together, the present study demonstrates that both meth-induced MAO- and L-type Ca2+ channel-dependent mitochondrial stress are necessary for chronic meth-induced neurodegeneration.

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

Chronic methamphetamine-induced neurodegeneration: Differential vulnerability of ventral tegmental area and substantia nigra pars compacta dopamine neurons

Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in substantia nigra pars compacta (SNc) axons; chronic administration produces SNc degeneration that is prevented by MAO inhibition suggesting that MAO-dependent axonal mitochondrial stress is a causal factor. To test whether meth similarly increases mitochondrial stress in ventral tegmental area (VTA) axons, we used a genetically encoded redox biosensor to assess mitochondrial stress ex vivo. Meth increased MAO-dependent mitochondrial stress in both SNc and VTA axons. However, despite having the same meth-induced stress as SNc neurons, VTA neurons were resistant to chronic meth-induced degeneration indicating that meth-induced MAO-dependent mitochondrial stress in axons was necessary but not sufficient for degeneration. To determine whether L-type Ca2+ channel-dependent stress differentiates SNc and VTA axons, as reported in the soma, the L-type Ca2+ channel activator Bay K8644 was used. Opening L-type Ca2+ channels increased axonal mitochondrial stress in SNc but not VTA axons. To first determine whether mitochondrial stress was necessary for SNc degeneration, mice were treated with the mitochondrial antioxidant mitoTEMPO. Chronic meth-induced SNc degeneration was prevented by mitoTEMPO thereby confirming the necessity of mitochondrial stress. Similar to results with the antioxidant, both MAO inhibition and L-type Ca2+ channel inhibition also prevented SNc degeneration. Taken together the presented data demonstrate that both MAO- and L-type Ca2+ channel-dependent mitochondrial stress is necessary for chronic meth-induced degeneration.

Mitochondrial oxidant stress mediates methamphetamine neurotoxicity in substantia nigra dopaminergic neurons

Methamphetamine abuse is associated with an increased risk of developing Parkinson's disease (PD). Recently, it was found that methamphetamine increases mitochondrial oxidant stress in substantia nigra pars compacta (SNc) dopaminergic neurons by releasing vesicular dopamine (DA) and stimulating mitochondrially-anchored monoamine oxidase (MAO). As mitochondrial oxidant stress is widely thought to be a driver of SNc degeneration in PD, these observations provide a potential explanation for the epidemiological linkage. To test this hypothesis, mice were administered methamphetamine (5 mg/kg) for 28 consecutive days with or without pretreatment with an irreversible MAO inhibitor. Chronic methamphetamine administration resulted in the degeneration of SNc dopaminergic neurons and this insult was blocked by pretreatment with a MAO inhibitor – confirming the linkage between methamphetamine, MAO and SNc degeneration. To determine if shorter bouts of consumption were as damaging, mice were given methamphetamine for two weeks and then studied. Methamphetamine treatment elevated both axonal and somatic mitochondrial oxidant stress in SNc dopaminergic neurons, was associated with a modest but significant increase in firing frequency, and caused degeneration after drug cessation. While axonal stress was sensitive to MAO inhibition, somatic stress was sensitive to Cav1 Ca2+ channel inhibition. Inhibiting either MAO or Cav1 Ca2+ channels after methamphetamine treatment attenuated subsequent SNc degeneration. Our results not only establish a mechanistic link between methamphetamine abuse and PD, they point to pharmacological strategies that could lessen PD risk for patients with a methamphetamine use disorder.

Spiny Projection Neuron Dynamics in Toxin and Transgenic Models of Parkinson's Disease.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder that results from the progressive degeneration of substantia nigra pars compacta (SNc) dopamine (DA) neurons. As a consequence of SNc degeneration, the striatum undergoes DA depletion causing the emergence of motor symptoms such as resting tremor, bradykinesia, postural instability and rigidity. The primary cell type in the striatum is the spiny projection neuron (SPN), which can be divided into two subpopulations, the direct and indirect pathway; the direct pathway innervates the substantia nigra pars reticulata and internal segment of the globus pallidus whereas the indirect pathway innervates the external segment of the globus pallidus. Proper control of movement requires a delicate balance between the two pathways; in PD dysfunction occurs in both cell types and impairments in synaptic plasticity are found in transgenic and toxin rodent models of PD. However, it is difficult to ascertain how the striatum adapts during different stages of PD, particularly during premotor stages. In the natural evolution of PD, patients experience years of degeneration before motor symptoms arise. To model premotor PD, partial lesion rodents and transgenic mice demonstrating progressive nigral degeneration have been and will continue to be assets to the field. Although, rodent models emulating premotor PD are not fully asymptomatic; modest reductions in striatal DA result in cognitive impairments. This mini review article gives a brief summary of SPN dynamics in animal models of PD.

Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease

Current drugs used in the treatment of Parkinson's disease (PD), for example, L-DOPA and dopamine agonists, are very effective at reversing the motor symptoms of the disease. However, they do little to combat the underlying degeneration of dopaminergic neurones in the substantia nigra pars compacta (SNc) and their long-term use is associated with the appearance of adverse effects such as L-DOPA-induced dyskinesia. Much emphasis has therefore been placed on finding alternative non-dopaminergic drugs that may circumvent some or all of these problems. Group III metabotropic glutamate (mGlu) receptors were first identified in the basal ganglia a decade ago. One or more of these receptors (mGlu4, mGlu7 or mGlu8) is found on pre-synaptic terminals of basal ganglia pathways whose overactivity is implicated not only in the generation of motor symptoms in PD, but also in driving the progressive SNc degeneration. The finding that drugs which activate group III mGlu receptors can inhibit transmission across these overactive synapses has lead to the proposal that group III mGlu receptors are promising targets for drug discovery in PD. This paper provides a comprehensive review of the role and target potential of group III mGlu receptors in the basal ganglia. Overwhelming evidence obtained from in vitro studies and animal models of PD supports group III mGlu receptors as potentially important drug targets for providing both symptom relief and neuroprotection in PD.

C-Jun N-Terminal Kinase Mediates Lactacystin-Induced Dopamine Neuron Degeneration

Parkinson disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been proposed that dysfunction of the ubiquitin proteasome system plays an important role in the pathogenesis of Parkinson disease, but the mechanisms underlying ubiquitin proteasome system-related neuron degeneration are unknown. Here, we demonstrate that the proteasome inhibitor lactacystin induces phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, the release of cytochrome c, activation of both caspase-9 and caspase-3, and sequential apoptosis of dopaminergic neurons in vitro. Most of these effects can be attenuated by the JNK inhibitor SP600125. Furthermore, infusion of lactacystin in rats in vivo also leads to phosphorylation of JNK before nigral neuron loss; chronic administration of SP600125 also blocks this loss. These results indicate that JNK is involved in proteasome inhibition-induced dopaminergic neuron degeneration through caspase-3-mediated apoptotic pathways, suggesting that this kinase may be a therapeutic target for the prevention of substantia nigra pars compacta degeneration in Parkinson disease patients.

Lesion of substantia nigra pars compacta by the GluR5 agonist ATPA

Dopamine (DA) released by substantia nigra pars compacta (SNc) neurons is a key regulator of motor activity. A deficiency in the striatum DA content due to SNc degeneration is a characteristic of Parkinson’s disease. The involvement of excitotoxic mechanisms in this pathology has been suggested. The kainate receptor subunit GluR5 has been identified in a few basal ganglia but it is strongly expressed in SNc. Here we examine whether ( RS)-2-amino-3-(3-hydroxy-5- t butylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist of GluR5, induces damage in dopaminergic (DAergic) neurons. ATPA (13 nmol) was administered to rat SNc. Immediately after recovery from surgery, the rats displayed ipsilateral turning. This behavior disappeared in subsequent days. The administration of the D1/D2 agonist, apomorphine (1 mg/kg, s.c.) 1 and 2 weeks after ATPA-infusion also induced ipsilateral turning. Histological studies—performed 21 days after ATPA-infusion—showed a lesion of the lateral and central part of the SNc, where a significant loss (36%) of DAergic cells was detected by tyrosine hydroxylase immunohistochemistry. The lesion was restricted to the SNc, since no damage or glial reaction was observed in the substantia nigra pars reticulata as assessed by Nissl staining, tomato lectin staining for microglial cells and GFAP immunohistochemistry for astrocytes. In conclusion: (1) ATPA-infusion induces neuronal damage in the SNc in the rat and (2) the behavioral effects of unilateral infusion of ATPA are consistent with DAergic alterations in basal ganglia.

Simultaneous Intrastriatal 6-Hydroxydopamine and Quinolinic Acid Injection: A Model of Early-Stage Striatonigral Degeneration

Animal models reproducing early stages of striatonigral degeneration (SND), the core pathology underlying parkinsonism in multiple system atrophy, are lacking. We have developed a new model of early-stage SND by using a simultaneous unilateral administration of quinolinic acid (QA) and 6-hydroxydopamine (6-OHDA) into the putaminal equivalent of the rat striatum. Spontaneous and drug-induced behavior, thigmotactic scanning, paw reaching deficits, and histopathology were studied in rat groups: group 1 (control), group 2 (QA), group 3 (6-OHDA), and group 4 (QA + 6-OHDA). The double toxin administration resulted in reduction of the spontaneous and the amphetamine-induced ipsiversive bias in the 6-OHDA group and in a reduction of the apomorphine-induced ipsiversive rotations in the QA group. Simultaneous QA and 6-OHDA also reduced the thigmotactic bias observed in the 6-OHDA rats. Combined toxin elicited a nonsignificant contralateral deficit in paw reaching but a significant deficit on the ipsilateral side. Histopathology revealed a significant reduction of the lesioned striatal surface (−27%) with neuronal loss and increased astrogliosis in group 4 compared to group 2, consistent with an exacerbation of QA toxicity by additional 6-OHDA. By contrast, the mean loss of the TH-positive neurons in the ipsilateral substantia nigra pars compacta (SNc) of group 4 was less marked (−15%) than in the 6-OHDA group (−36%), indicating a possible protective action of intrastriatal QA upon 6-OHDA retrograde SNc degeneration. This study shows that a combined unilateral intrastriatal administration of QA and 6-OHDA may serve as a model of early stage SND which is more suitable for early therapeutic interventions.