The Role of Monoamine Oxidase B Inhibitors in the Treatment of Parkinson’s Disease – An Update

Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by reduced dopamine level in the substantial nigra. This may lead to typical motor features such as bradykinesia, resting tremors and rigid muscles; as well as non-motor symptoms such as neuropsychiatric symptoms, sleep disorders, autonomic dysfunction, and sensory disturbances. Inhibitors of MAO-B are used to alleviate symptoms by reducing monoamine oxidase-catalysed degradation of dopamine; hence, preserving functional levels of dopamine. The very first MAO-B used therapeutically was selegiline, followed by rasagiline, its indane derivative which has superior efficacy and selectivity. Both inhibitors can be used as monotherapy or in combination with other anti-Parkinson drugs. Safinamide, a reversible MAO-B inhibitor that utilises both dopaminergic and non-dopaminergic mechanisms, was recently approved by the European Medicines Agency (EMA) (2015) and U.S. FDA (2017) as an add-on therapy for patients with mid- or late-stage Parkinson’s disease. Furthermore, MAO-B inhibitors were found to be associated with potential neuroprotective and disease modifying effects. However, evidence of their efficacy and role in PD models are scarce and warrants further investigation.

Metabolite Alternations in the Dopamine Circuit Associated with Methamphetamine-Related Psychotic Symptoms: A Proton Magnetic Resonance Spectroscopy Study

Objective: Chronic METH use results in neurodegenerative alternations in the human brain. The present study aimed to assess the long-term METH impact on brain metabolite concentrations in cases meeting the DSM-5 criteria regarding METH use. Method: We recruited 42 METH users meeting the DSM-5 criteria and 21 healthy controls. Psychotic signs were measured using the Positive and Negative Syndrome Scale (PANSS). Proton magnetic resonance spectroscopy (1HMRS) evaluating Myo-inositol (Ml), Choline (Cho), Glutamine plus Glutamate (Glx), N-acetyl aspartate (NAA), and Creatine (Cre) were obtained in the dopaminergic pathway (Frontal Cortex, Substantia nigra, Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), Hippocampus, Striatum,) the subjects. All participants collected urine specimens for 24 hours to measure presence of specific metabolites including METH metabolite level, 5-Hydroxy indoleacetic acid metabolite (for serotonin level monitoring), and metanephrine metabolite (for dopamine level monitoring). Results: Dopamine and Serotonin increased in the METH group (P < 0.001). METH caused an increase in the Cre (P < 0.001) and a decline in the Glx (P < 0.001), NAA (P = 0.008), and MI (P < 0.001) metabolite concentrations of dopamine circuits in METH users in comparison with healthy subjects. We found no change in Cho metabolite concentration. Psychological data and the neurometabolite concentrations in the studied area of the brain were significantly correlated. Conclusion: There is an association between METH use and active neurodegeneration in the dopamine circuit, and it causes serious mental illness. 1HMRS can detect patient’s deterioration and progression of disease as well as follow-up management in patients with METH use disorder.

l-Menthol increases extracellular dopamine and c-Fos-like immunoreactivity in the dorsal striatum, and promotes ambulatory activity in mice

Similar to psychostimulants, the peripheral administration of menthol promotes mouse motor activity, and the neurotransmitter dopamine has been suggested to be involved in this effect. The present study aimed to elucidate the effects of l-menthol on parts of the central nervous system that are involved in motor effects. The subcutaneous administration of l-menthol significantly increased the number of c-Fos-like immunoreactive nuclei in the dorsal striatum of the mice, and motor activity was promoted. It also increased the extracellular dopamine level in the dorsal striatum of the mice. These observations indicated that after subcutaneous administration, l-menthol enhances dopamine-mediated neurotransmission, and activates neuronal activity in the dorsal striatum, thereby promoting motor activity in mice.

Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects

Background Impulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects. Methods A total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits. Results Negative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity. Conclusions FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.

Impact of Obesity on Physical Activity

BACKGROUND: Obesity occurs due to an imbalance between the calories and the energy released. On the animal model, obesity is considered as the ground for low physical activity. This is caused by low dopamine D2 receptor in the striatum. However, this suggestion is still unproven in the human condition. AIM: The aim of this study was to find out difference in dopamine expression in obese subjects compared to non-obese subjects when triggered by the stimuli of physical activity. METHODS: This is a quasi-experimental study. The sample was obese and non-obese (control) female who met inclusion and exclusion criteria. Before treatment was given, subjects were asked to fill out a depression, anxiety, and exercise motivation questionnaire. All subjects were tested for vital signs, anthropometrics, and neurological examinations to determine the initial condition. Then, the subjects saw video about physical activity and were taken for blood to measure blood dopamine levels using enzyme-linked immunosorbent assay. Differences in dopamine levels between the obese and control groups were analyzed using independent t-test. The relationship between dopamine levels and exercise motivation was analyzed using Pearson. RESULTS: The obese group’s dopamine level was 71.19 ±3.02ng/ml and the control group was 81.15 ± 3.17ng/ml (independent t-test, p = 0.032). The obese group’s motivation score was 58.46 ± 1.59 and the control group score was 62.38 ± 1.54 (independent t-test, p = 0.09). Furthermore, there was no correlation between dopamine levels and motivation scores (Pearson test, p = 0.09). CONCLUSION: There are significant differences in dopamine levels between the obese group and the control group but no correlation between dopamine levels and exercise motivation scores.

Neuroprotective Effect of Celastrus Paniculatus Seed Extract in Epilepsy and Epilepsy-Associated Cognitive Deficits

Purpose: Cognitive deficit is one of the common comorbidity accompanying epilepsy. The present study evaluated the effect of Celastrus paniculatus (C- paniculatus) seed extract on seizure severity and cognitive deficit following Pentylenetetrazole (PTZ) -induced chemical kindling model. Methods : PTZ kindling model was developed by daily administration of sub-convulsive dose of PTZ 30 mg/kg for 4 weeks. After 4 weeks of induction, the following treatment namely Sodium valproic acid (SVA) 200 mg/kg, C- paniculatus 500 mgkg, Pergolide 2 mg/kg alone and combination groups C- paniculatus 250 mgkg+ Pergolide 1 mg/kg and C- paniculatus 250 mgkg+ SVA 100 mg/kg were administered 30 minute prior to PTZ 30 mg/kg injection for a period of next 14 days. Neurobehavioral parameters Morris water maze test (MWM), Grip strength test (GPS) brain superoxide dismutase (SOD), Catalase, reduced glutathione (GSH) and dopamine level. Hematoxylin & Eosin (H&E) staining of hippocampus pyramidal layers Cornu ammonis (CA1), CA2, CA3, dentate gyrus (DG), and frontal cortex were assessed. Results: C- paniculatus 500 mg/kg alone and combination groups C- paniculatus 250 mgkg+ Pergolide 1 mg/kg and Celastrus paniculatus 250 mgkg+ SVA 100 mg/kg significantly (p<0.05) reduced the seizure score, mean latency time, and distance traveled in MWM. However, no significant effect was seen in grip strength test. Biochemical analysis showed elevated antioxidant markers namely GSH, catalase, and SOD & elevated dopamine levels. C- paniculatus and its combination were also found significantly (p<0.05) protected against neuronal loss in hippocampus and frontal cortex as evidenced by H&E staining. Conclusion: C- paniculatus alone and its combination may have the potential to treat epilepsy and associated cognitive deficits.

Neuroprotective effect of methanolic extract of Sargassum wightii on rotenone-induced parkinsonism-like symptoms in Wistar albino rats

Introduction: The pathogenesis of Parkinson’s disease (PD) is multifactorial in which oxidative stress, neuroinflammation, and mitochondrial dysfunction are the leading factors. Currently, the antioxidant and anti-inflammatory agents of natural sources as neuroprotectants have raised much attention. The current study aimed to explore the neuroprotective effect of methanolic extract of Sargassum wightii in male Wistar albino rats against rotenone-induced PD. Methods: The rats were administered with rotenone (10 mg/kg orally) daily for 28 days to induce PD. S. wightii (200 mg/kg and 400 mg/kg) and levodopa+carbidopa combination (10 mg/kg) were administered to different groups of rats one hour prior to rotenone for 28 days. Behavioral parameters (akinesia, tremor, motor coordination, and locomotor activities) and body weight were recorded on days 14th and 28th of drug treatment. On the 28th day, the animals were sacrificed for the neurobiochemical analyses of brain tissue. Results: Rotenone treatment caused a significant reduction in behavioural parameters (P < 0.001), neurochemical deficits (P < 0.001), and elevation of oxidative stress markers (P < 0.001) in the brain. Pre-treatment with S. wightii at 200 mg/kg and 400 mg/kg doses significantly attenuated the rotenone-induced behavioral alterations and restored the mitochondrial NADH dehydrogenase activity and dopamine level in the striatum (P < 0.001). Moreover, 400 mg/kg of S. wightii restored the rotenone-induced increased oxidative stress markers like malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) in the striatum (P < 0.01). Conclusion: S. wightii has provided a neuroprotective effect, probably by virtue of its antioxidant and dopamine restoring potential. Hence, it may offer a promising and new therapeutic lead for the treatment of PD but needs further research.

Neurological behaviour of albino rats treated separately and in combination with Cannabis sativa L. and Cannabis indica L.

There has been an increasing rate of cannabis consumption globally, especially among the youths. This study therefore evaluated the neurological behaviours and some brain marker hormones and enzymes of cannabis administered rats. Twenty six albino rats were divided into four groups based on oral cannabis administration (control, Cannabis sativa, Cannabis indica and the combination of the two). At the end of seven days, open field test was conducted on the rats. Also, brain neuro-chemicals, activities of antioxidant enzymes and lipid peroxidation were evaluated using spectrophotometry. The results of the Open-Field Test showed an appreciable increase in the level of ambulation (line crossing), grooming, urination and stretched attend posture in the rats administered with Cannabis indica, Cannabis sativa and the combination when compared with the control. Norepinephrine was significantly lower (p < 0.05) in the rat groups administered with the combination of Cannabis indica and Cannabis sativa. The control group however had the lowest dopamine level. Superoxide dismutase (SOD) was significantly lower (p < 0.05) in the rats administered the combination of both Cannabis indica and Cannabis sativa. The brain level of reduced glutathione (GSH) was significantly higher in the rats administered with Cannabis indica. Malondialdehyde (MDA) was significantly higher in the rats administered with Cannabis sativa than the other rat groups. Histopathological evaluation of the brain also revealed various damages in the brain cells of rats administered with cannabis compared to the normal brain structure of the control rats. It is thus said that consumption of C. sativa or C. indica alone produced mild effect on the brain cells and physiology in rats. However, combination of C. sativa and C. indica produced a severe synergistic effect on the neurological function of the exposed rat.

Early-life stress induces prodromal features of Parkinsonian with aging in rats

Early-life stress (ELS) can cause long-term effects on human health, ranging from adolescence to adulthood, and even to gerontic. Although clinical retrospective data suggest that ELS may be related to senile neurodegenerative diseases such as Parkinson’s disease (PD), there are few prospective investigations to explore its real contribution to PD. Here, we investigated the behavioral, histochemistical, neuromorphological and transcriptional changes induced by maternal separation (MS), an ELS model. Without neurotoxin, MS rats showed behavioral alterations in olfaction, locomotion and gait characters after depression compared with control rats. Based on neuroimaging and histochemistry, although we found that the dopaminergic system in striatum was impaired after MS, the decrease of striatal dopamine level was ~33%. Consistently, tyrosine hydroxylase immune-staining positive neurons of MS rats in the substantia nigra showed deficit by about 20% in cell counting. Furthermore, using transcriptome sequencing, we discovered many differentially expressed genes (DEGs) of MS rats in striatum significantly enriched in the pathway of dopaminergic synapse, and the biological process of locomotion and neuromuscular process controlling balance. Encouragingly, some representative DEGs relating to PD were singled out. These results suggest that ELS-depression rats potentially mimic some key features of prodromal stage of PD during natural senescence. In conclusion, our findings provide some novel insights into the future pathogenesis and therapeutic studies for PD related to depression.