Midbrain Research Articles

Genome sequencing projects reveal new insights into the mammalian Gonadotropin-releasing Hormone II system.

The type II gonadotropin-releasing hormone (GnRH-II) was first discovered in chicken (Gallus gallus) brain and then shown to be present in many vertebrates. Indeed, its structure is conserved unchanged throughout vertebrate evolution from teleost fish through to mammals suggesting a crucial function. Yet the functional significance has been largely unexplored. Studies in comparative endocrinology show that the GnRH-II system is differentially functional in mammalian species. Intact GnRH-II neuropeptide and receptor genes (GnRH2 and GnRH receptor 2 GnRHR2) occur in marmoset monkeys (Callithrix jacchus), musk shrews (Suncus murinus) and pigs (Sus scrofa). However, one or other or both of these genes are inactivated in other species, where mutations or remnants affecting GnRH2 neuropeptide and/or type II GnRHR exons are retained in conserved genomic loci. New data from DNA sequencing projects facilitate extensive analysis of species-specific variation in these genes. Here, we describe GnRH2 and GnRHR2 genes spanning a collection of 21 taxonomic orders, encompassing around 140 species from Primates, Scandentia, Eulipotyphla, Rodentia, Lagomorpha, Artiodactyla, Carnivora, Perissodactyls, Pholidota, Chiroptera, Afrotheria, Xenarthra and Marsupialia. Intact coding exons for both GnRH2 and GnRHR2 occur in monkeys, tree shrews, shrews, moles, hedgehogs, several rodents (degu, kangaroo-rat, pocket mouse), pig, pecarry and warthog, camels and alpaca, bears, Weddell seal, hyena, elephant, aardvark and marsupials. Inactivating mutations affecting GnRH2 and GnRHR2, some located at conserved sites within exons, occur in species of primates, most rodents, lagomorphs, bovidae, cetaceans, felidae, canidae and other carnivora, pangolins, most bats, armadillo, brushtail and echidna. A functional GnRH-II system appears retained within several taxonomic families of mammals, but intact retention does not extend to whole taxonomic orders. Defining how endogenous GnRH-II neuropeptide operates in different mammals may afford functional insight into its actions in the brain, especially as, unlike the type I GnRH system, it is expressed in the mid brain and not the hypothalamus.

Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRb/E2F1 pathway in a model of Parkinson's disease

Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.

Dietary Natural Flavonoids: Intervention for MAO-B Against Parkinson's Disease.

Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α-synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO-A and MAO-B, responsible for the oxidation of monoamines such as dopamine. Increased MAO-B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD-like manifestations. Inhibitors of MAO-B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO-B inhibitors such as selegiline, L-deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO-B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO-B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO-B inhibitors. The discussion encompasses both invitro and invivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO-B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD-like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO-B inhibitory activity and additionally multi-targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches.

Serum uric acid is associated with midbrain enlarged perivascular spaces: Results from Multi-modality Medical imaging sTudy bAsed on KaiLuan Study (META-KLS)

BackgroundSerum uric acid (SUA) is a major cause of cardiovascular and cerebrovascular diseases. Whether and to what extent the excess risk of enlarged perivascular spaces (EPVS) conferred by SUA is unknown. The study was conducted to investigate the association between SUA and EPVS in different brain regions. MethodsData are from Multi-modality medical imaging study based on Kailuan study (META-KLS) in this cross-sectional study. Participants were divided into five groups based on SUA levels, and EPVS in basal ganglia (BG), centrum semiovale (CSO) and midbrain (MB) was systematically assessed and divided into Low and High group. Odds ratio (OR) and 95% confidence intervals (95% CIs) for high EPVS outcomes were estimated using multivariable logistic regression analysis. Restricted cubic spline (RCS) was used to further investigate dose-response relationship. ResultsA total of 1014 participants aged 25–83 years from 11 centers were enrolled in the study. In the multivariable-adjusted model, SUA, as an independent risk factor, correlated positively with high degree of MB-EPVS (OR, 1.002; 95% CI, 1.000 to 1.004; p = 0.023) in general population. In addition, RCS further demonstrated the linear association between SUA and MB-EPVS (p = 0.072). No association was found between SUA and BG-EPVS or CSO-EPVS. ConclusionSUA was an independent risk factor of MB-EPVS. High SUA levels were more predictive of increased risk occurrence of high degree of MB-EPVS, supporting a linear association between SUA and MB-EPVS and further indicating that SUA may play an important role in cerebral small vessel disease. Trial registrationThe KaiLuan Study and META-KLS were registered online (ChiCTR2000029767 on chictr.org.cn and NCT05453877 on Clinicaltrials.gov, respectively).

A Case Report in the Management of Dysphagia in Osmotic Demyelination Syndrome Using Mann Assessment of Swallowing Ability (MASA).

Osmotic Demyelination Syndrome (ODS) is one of the primary cause of demyelination in alcoholics and malnourished resulting in various kind of clinical manifestations in pontine symptoms, neuro-behavioural symptoms movement disorders as well as speech and language and swallowing difficulties. The study was done to introspect the prognosis of swallowing therapy in a patient with ODS using MASA (Mann Assessment of Swallowing Ability). A 36years old male with a history of regular alcohol intake and hypertensiom reported in our healthcare centre with hypoaklemia and speech, language and swallowing difficulty. Magnetic resonance imaging of the brain showed bilateral symmetrical T2 and T2 FLAIR (fluid attenuated inversion recovery) hyperintensity lesion in the bilateral basal ganglia involving the caudate nuclei, putaminal region and bilateral thalami with similar lesion along the mid brain. There were no areas of acute restriction in diffusion study. The findings suggested of Osmotic Demyelination Syndrome (ODS).When accessed with N-DAT, WAB and MASA; patient was diagnosed with Spastic Dysarthria, Transcortical Motor Aphasia and Moderate Dysphagia. Intervention was provided using speech and swallowing therapy and when introspected with MASA scores, improvement was seen within 5days and statistically 97% of variance was seen inferring the progressing trend in the MASA scores. This study concludes that MASA can be an effective tool in introspecting the prognosis of Dysphagia in ODS and early intervention in the management of dysphasia shows positive results.

Effects of enlarged perivascular space in Parkinson’s disease and related cognitive decline

AbstractBackgroundThe glymphatic system plays a key role in brain toxics clearance. Many studies demonstrated that disrupted glymphatic system is responsible for insufficient clearance of Aβ and tau protein in Alzheimer’s disease. Its contribution in Parkinson’s disease (PD) and related cognitive function decline has not been fully studied. Enlarged perivascular space (PVS) may be a sign of glymphatic function decline, hence leading to PD pathology and PD‐related cognitive function decline. Our objective was to study the PVS in PD and related cognitive function decline.MethodHigh‐resolution T1‐weighted and T2‐weighted MRI data were acquired from 60 PD patients and 58 age‐ and sex‐matched controls. The PVS from the centrum semiovale of the white matter (CS), striatum (ST) and midbrain (MB) of the basal ganglia were segmented using the enhanced images from T1‐ and T2‐weighted images. Total intracranial volumes (TIV) were obtained to account for individual head sizes. Montreal Assessment of Cognition (MoCA) was used to quantify cognitive function. MDS‐UPDRS III scores were obtained for motor function deficits. ANCOVA was used to compare PVS metrics between PD patients and controls adjusted for age, sex, and TIV. Multiple regression was used to corelate PVS metrics and MoCA in PD patients with age, sex, MDS‐UPDRS III score and TIV as covariates.ResultCompared to controls, PD patients had enlarged PVS in MB (p = 0.0028), but not in CS and ST. PVS metrics were strongly associated with age (p < 0.0001 for CS, p < 0.0001 for ST, and p = 0.0092 for MB), but only PVS in MB was associated sex (p = 0.0001). In PD patients, the MoCA was associated with the PVS in CS (p = 0.0132), MB (p = 0.0275) and total PVS (p = 0.0088) but only trending with PVS in ST (p = 0.0737). There is no association between MoCA and PVS metrics in controls.ConclusionOur findings suggested that PD patients have enlarged PVS in the midbrain, and their cognitive function is associated with enlarged PVS in both CS and MB. The enlarged PVS might be an etiological factor for PD pathology and related cognitive decline.

OA12 Grimey granulomas of sarcoidosis

Abstract Introduction Sarcoidosis affects approximately 1% of the population. There are two situations where it came become life threatening: seizures secondary to neuro-sarcoidosis and arrhythmias due to cardiac infiltration. Currently there are limited licenced therapies for the treatment of sarcoidosis. We describe a case of cutaneous and neuro-sarcoidosis who developed subsequent multi-system sarcoidosis. Case description A previously fit and well 50-year-old presented to his local hospital with tonic clonic seizures. He worked as a mortgage broker and never smoked. There was no pro-drome and on examination it was noted he had erythema nodosum on his shins. He was investigated with a CT head and subsequent MRI demonstrating enhancement of his leptomeninges, mid brain parenchyma, hypothalamus and pituitary gland. A lumbar puncture was performed with an elevated protein level of 934g with a normal glucose and lymphocyte level. The CSF was negative for TB. A CT of his chest was performed demonstrating bilateral hilar lymphadenopathy and subsequent histology of these lymph nodes demonstrated non-necrotising, non-caseating epithelioid granulomas. A diagnosis of sarcoidosis was made and he was commenced on mycophenolate. His disease remained quiescent for 5 years before the eruption of further skin lesions. He developed multiple subdermal nodules on his fingers, wrists, elbows which were biopsied demonstrating cutaneous sarcoidosis. Neurological examination demonstrated brisk lower limb reflexes with upgoing plantars. He was commenced on a tapering course of prednisolone and an evaluation for extra-cutaneous disease was made. An IL2Ra was 4719ng/L (423-1843) with a normal ACE. Pituitary axis testing revealed a slightly raised prolactin (326 mIU/L). A CT-PET was performed demonstrating extensive metabolic activity in his skin, central nervous system, liver, spleen, salivary glands, skeletal uptake in both humeral heads alongside myocardial uptake. An urgent cardiac MRI was performed demonstrating active myocardial disease. An ECG did not demonstrate any conduction abnormalities. A diagnosis of multi-system sarcoidosis was made warranting an urgent MDT discussion given the progression of his disease. Discussion In this particular case, it had been assumed that his sarcoidosis was inactive until the emergence of the skin lesions. It was the skin lesions that lead to an assessment for multi-system sarcoidosis. It is common for the serum ACE level to be normal, as seen in up to 50% of cases and it was the Il2Ra elevation that prompted the CT-PET request. Given the extent and progression of disease despite treatment with mycophenolate, this gentlemen was given a tapering regime of prednisolone (starting at 20mg) and his mycophenolate was switched to methotrexate which has shown to have superior efficacy to mycophenolate for sarcoidosis. Furthermore, infliximab at a dose of 5mg/kg was commenced shortly after to control the increasing CNS lesions. Infliximab is a well recognised treatment for sarcoidosis; however, due to limited clinical trial data, it remains unlicenced for use in sarcoidosis with the exception of neuro-sarcoidosis (following the failure of DMARD therapy). To date, the patient remains well with no further worsening in his disease. Key learning points Sarcoidosis is a clinical entity with no one specific test. The diagnosis should be constructed using multiple parameters including radiographic findings, biochemical and histological proof. We advocate that suspected cases of sarcoidosis should have a thorough assessment and discussion in the MDT. When isolated skin disease is suspected or confirmed, baseline testing for extra-cutaneous involvement should be sent including NT-proBNP, troponin I and T, creatinine kinase, a full pituitary profile, ACE and cytokine assessment for Il2Ra, amongst other routine blood tests. An ECG is of paramount importance as arrhythmias are common cardiac features of sarcoidosis. Should there be ongoing suspicion of multiple organ involvement, a CT-PET should be performed at baseline. Isolated lymph node disease does not commonly warrant treatment; however, this cohort of patients should be closely monitored. The management of sarcoidosis in the acute setting is commonly prednisolone, but steroid sparing therapies should be considered in patients needing recurrent, prolonged courses of corticosteroids or those with evidence of critical organ involvement such as CNS, cardiac or lung disease. Life threatening disease or disease refractory to DMARD therapy should be considered for anti-TNF therapy with infliximab or adalimumab. More recently, tofacitinib has been promising as a treatment for sarcoidosis with clinical trials in Yale and Portland. Newer therapies in development include the GM-CSF inhibitor namilumab, and efzofitimod, a neuropilin 2 inhibitor.

Dose-dependent delivery of genes to the cerebral cortex via the nasal route

The use of nucleic acids to treat various brain diseases could offer new therapeutic modalities, providing the nucleic acids may be effectively delivered to areas of the brain using non-toxic vectors. In this study, we present evidence that genes may be successfully delivered in a dose-dependent manner via the nose, primarily to the cerebral cortex using a 6-O-glycolchitosan (GC) formulation of plasmid DNA. Positively charged (zeta potential = +13 - + 25 mV) GC-DNA nanoparticles of 100–500 nm in diameter with favourable cell biocompatibility were shown to deliver the reporter Green Fluorescent Protein (GFP) plasmid to the U87MG cell line and the resulting protein expression was not significantly different from that obtained with Lipofectamine 2000. On intranasal delivery of GC-luciferase-plasmid nanoparticles to Balb/ C mice at 4 doses, ranging from 0.02 to 0.1 mg/ kg, luciferase activity was observed qualitatively in intact mouse brains, 48 h after intranasal, using the IV-VIS visualisation. In further confirmation of brain delivery, dose-dependent protein expression was quantified in multiple brain areas 48 h after dosing; with protein expression seen mainly in the cerebral cortex and striatum and following expression levels: cerebral cortex = olfactory bulb > striatum > brain stem > mid brain = cerebellum. No protein expression was observed in the liver and lungs of dosed animals. GC-DNA protein expression was not significantly different to that observed with Lipofectamine 2000. These results demonstrate that GC-DNA nanoparticles are able to deliver genes preferably to specific brain regions such as the cerebral cortex and striatum; offering the possibility of using genes to treat a range of neurological disorders using a non-invasive method of dosing.

Neuromyelitis Optica Spectrum Disorder (Device’s Disease): - A Case Report Of Full Recovery With Corticosteroids, Therapeutic Plasmapheresis And Immunotherapy

Neuromyelitis optica is a severely disabling inflammatory disorder of autoimmune etiology of the central nervous system, mainly affecting the optic nerves and spinal cord. Here, we present a case report of neuromyelitis optica in a 28-year-old Indian woman who presented with sudden painless loss of vision with tingling followed by weakness of all four limbs with bowel involvement that developed over a period of one week, with a significant history of recent vaccination with COVISHIELD (ChAdOx1 nCoV- 19) vaccine . Clinical evaluation showed diminished vision in both eyes, which progressed to loss of power across all major muscle groups in all limbs and bowel involvement. Magnetic resonance imaging of brain with contrast was done which showed T2W/FLAIR hyperintense non enhancing signal in bilateral thalami extending caudally in mid brain on left side and in midline anterior medulla with subtle T2 hyperintense signal in body of corpus callosum, similar foci are seen in bilateral frontoparietal white matter suggestive of ADEM or demyelination. Also T2 hyperintense signal in both optic nerves [left> right] in posterior part of orbit suggestive of optic neuritis. MRI whole spine showed multiple patchy hyperintense signals on T2 and hypointensity on T1 all over cervical and dorsal vertebrae through whole segment in contiguous manner. The patient was immediately started on intravenous methylprednisolone pulse therapy followed by plasmapheresis and immunomodulator therapy. The diagnosis of neuromyelitis optica was later confirmed with strongly positive neuromyelitis optica immunoglobulin G. Since, treatment was started early patient responded very well and made full recovery. Hence, early initiation of aggressive immunosuppressive treatment is essential in such cases.

Field Based Assessment of Clinical Signs of Irreversible Loss of Consciousness and Death Confirmed by Brain Destruction in Juvenile American Alligators (Alligator mississippiensis) After Penetrating Captive Bolt Stunning or Electrostunning with Probe Pithing

ABSTRACT To determine the humane use of slaughter methods we examined the clinical signs of life in 61 American alligators harvested on-farm using one of three methods: (i) captive bolt and spinal cord severance; (ii) electrostunning, spinal cord severance and pithing; and (iii) spinal cord severance and pithing. Loss of consciousness and the six clinical signs of life that can be used on-farm were assessed for evidence of irreversible unconsciousness and death at Time 0, 0.5, 1, 2, 5, 10, 20, and 30 min post slaughter. The brains of alligators from each slaughter method were removed to assess brain tissue disruption. A combination of loss of blink reflex, pupillary light response, jaw tone and respiration are a reliable on-farm tool for determining death. Heartbeat and withdrawal reflex persisted. Captive bolt and electrostunning methods were effective in immediately producing loss of response consistent with irreversible unconsciousness, subsequent death and destruction of neural tissue integrity in the mid and hind brain. They are therefore humane forms of slaughter in American alligators.

SEROTONIN IN THE MEDIATION OF BEHAVIORAL EFFECTS OF OMEGA-3 FISH OIL SUPPLEMENTS: A STUDY IN RATS.

Omega-3 polyunsaturated fatty acids (omg-3 PUFAs) are widely prescribed for improving therapeutic strategies in many diseases. There are reports that the use of these supplements can reduce disease-related depression and anxiety in patients taking these supplements. However, pre-clinical research shows mixed results. In view of the role of serotonin (5-hydroxytryptamine, 5-HT) in anxiety and depression, the present study concern effects of omg-3 on anxiety-like behavior and on serotonin metabolism in brain regions known to have a role in anxiety. It was found that administration of omg-3 for 20 days did not alter food intake and body weight. The treatment reduced locomotor activity in an open field arena and enhanced anxiety-like behavior in an elevated plus-maze test. 5-HT concentration increased in the hippocampus (HPC) and midbrain (MB) but decreased in the prefrontal cortex (PFC). Levels of 5-hydroxyindoleacetic acid (5-HIAA) were decreased in these regions. The tryptophan levels were not affected in the PFC but increased in the HPC and MB at a low dose; suggesting that decreases of 5-HT and 5-HIAA were not due to a decrease in the availability of tryptophan. The present study implied that unnecessary use of omg-3 supplements can reduce serotonin neurotransmission via the PFC to predispose to anxiety.

Enlarged perivascular spaces in patients with migraine: a case-control study based on 3T MRI.

To explore whether MRI-visible enlarged perivascular spaces (EPVS) are associated with migraine and may serve as a predictor of migraine. Then further explore its correlation with migraine chronification. A total of 231 participants (healthy control [HC] = 57, episodic migraine [EM] = 59, chronic migraine [CM] = 115) were included in this case-control study. A 3T MRI device and the validated visual rating scale were used to assess the grades of EPVS in centrum semiovale (CSO), midbrain (MB), and basal ganglia (BG). Comparisons between the two groups were made using the chi-square or Fisher's exact tests to initially determine whether high-grade EPVS were associated with migraine and migraine chronification. A multivariate logistic regression model was constructed to further investigate the role of high-grade EPVS in migraine. The prevalence of high-grade EPVS in CSO and MB were significantly higher in patients with migraine than in HCs (CSO: 64.94% vs. 42.11%, P = 0.002; MB: 55.75% vs. 29.82%, P = 0.001). Subgroup analysis showed no statistical difference between patients with EM and CM (CSO: 69.94% vs. 62.61%, P = 0.368; MB: 50.85% vs. 58.26%, P = 0.351). Individuals with high-grade EPVS in CSO (odds ratio [OR]: 2.324; 95% confidence interval [CI]: 1.136-4.754; P = 0.021) and MB (OR: 3.261; 95% CI: 1.534-6.935; P = 0.002) were more likely to suffer from migraine. This case-control study showed that high-grade EPVS in CSO and MB in clinical practice with the underlying mechanism of dysfunction of the glymphatic system could be a predictor of migraine, but no significant correlation had been found with migraine chronification.

Synaptojanin1 Modifies Endolysosomal Parameters in Cultured Ventral Midbrain Neurons.

The accumulation of α-synuclein (α-syn)-enriched protein aggregates is thought to arise from dysfunction in degradation systems within the brain. Recently, missense mutations of SYNJ1 encoding the SAC1 and 5'-phosphatase domains have been found in families with hereditary early-onset Parkinsonism. Previous studies showed that Synj1 haploinsufficiency (Synj1+/-) leads to accumulation of the autophagy substrate p62 and pathologic α-syn proteins in the midbrain (MB) and striatum of aged mice. In this study, we aim to investigate the neuronal degradation pathway using the Synj1+/- MB culture from mouse pups of mixed sex as a model. Our data show that GFP-LC3 puncta formation and cumulative mKeima puncta formation are unaltered at baseline in Synj1+/- MB neurons. However, GFP-LAMP1 puncta is reduced with a similar decrease in endogenous proteins, including lysosomal-associated membrane protein (LAMP)1, LAMP2, and LAMP2A. The LAMP1 vesicles are hyperacidified with enhanced enzymatic activity in Synj1+/- MB neurons. Using a combination of light and electron microscopy (EM), we show that endolysosomal changes are primarily associated with a lack of SAC1 activity. Consistently, expressing the SYNJ1 R258Q mutant in N2a cells reduces the lysosome number. Interestingly, the endolysosomal defects in Synj1+/- neurons does not impact the clearance of exogenously expressed wild-type (WT) α-syn; however, the clearance of α-syn A53T was impaired in the axons of Synj1+/- MB neurons. Taken together, our results suggest axonal vulnerability to endolysosomal defects in Synj1-deficient MB neurons.

Treatment of Parkinson's disease in Iranian ancient medicine.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the world.1 It affects 1% of the population over 65 years. In PD patients it can be seen that almost 60% of dopaminergic neurons in the substantia nigra of the mid brain are lost.2 Due to the disease motor symptoms such as bradykinesia, rigidity and resting tremors exist.3 The most common drugs, albeit with side effects, used to treat this disease include: levodopa, selegiline, amantadine and so forth.4 Non of the current therapies can to exchange in neurodegenerative procedure of the disease, and just symptomatic treatment caried out to enhance the life quality in the diseases.1 The clinical symptoms and treatment strategies of the disease were described by different Iranian physicians in the past centuries. Iranian traditional physicians such as Abu Bakr Mohammad Ibn Zakariya Razi (9th−10th century AD) in book of Man La Yahzaroho al-Tabib,5 Seyyed Mohammad Hossein Aghili Khorasani (17th−18th century AD) in book of Makhzan al-Advieh6 and Mohammad Mumen Mir Mohammad Zaman Tonekaboni, (17th century AD) in book of Tohfat al-Mumenin,7 also mentioned pharmaceutical agents for treatment guidelines as following in Table 1 below: Considering of these elements may be give a new vision in the treatment of this disorder. Hossein Jalaei Nobari was involved in drafting the article and revising it critically for important intellectual content, and Jalil Rashedi was involved in concept, design of study and translation. We thank the staff of the traditional medicine library of Tabriz University of Medical Sciences. The authors declare no conflict of interest. The lead author (Jalil Rashedi) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Not applicable.

Serotonin transporter availability in physically aggressive personality disordered patients: associations with trait and state aggression, and response to fluoxetine.

Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals. The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine. We examined 5-HTT availability using positron emission tomography (PET) imaging with [11C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20mg daily (n = 9) or placebo (n = 6) for 12weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed. In IED patients, trait aggression was positively associated with [11C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [11C]DASB in IED patients. Greater baseline VST [11C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment. Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine.

A Simple and High Throughput Methodology for Simultaneous Determination of Levodopa and Carbidopa

Parkinson's disease (PD) is a degenerative disorder of the central nervous system. The motor symptoms of PD disease result from the death of dopamine-generating cells in a region of the mid brain and the dopamine precursor levodopa (L-Dopa) is used for the treatment. Carbidopa (Car) is administered in association with L-Dopa in pharmaceutical formulation as an inhibitor on the decarboxylase activity. Thus, their simultaneous determination is of great importance because of their co-existence in pharmaceutical preparations. Present study deals with a simple method development for simultaneous voltammetric determination of L-Dopa and Car at a pencil graphite electrode (PGE) via monitoring the reduction peak of L-Dopa and the second oxidation peak of Car. The sensitivity of the method was found comparable to other methods depending on the sophisticated electrode modifications and the limits of detection were calculated as sub micromolar levels.

Quantifying Dilated Perivascular Spaces in Children with Sickle Cell Disease

Introduction: The neurological complications of sickle cell disease (SCD) are particularly devastating and range from "overt stroke" to cerebral small vessel disease (CSVD), including silent cerebral infarction (SCI) and cognitive deficits despite the absence of magnetic resonance imaging (MR)-detectable evidence of cerebral injury. This suggests the possibility of additional, possibly covert, mechanisms of injury. Perivascular (Virchow-Robin) spaces (PVS) are fluid filled spaces that surround cerebral vessels penetrating or leaving the brain parenchyma and become visible when enlarged (dilated), due to inflammation or hypertension. The presence of dilated PVS (dPVS) in the basal ganglia (BG) and centrum semiovale (CO) are rare in children and have been associated with multiple neurodegenerative and neuroinflammatory disorders in aging populations. dPVS in the BG specifically are associated with CSVD, while those in the CO are associated with neuroinflammation. However, until now, the presence of dPVS has not been studied in either adults or children with SCD. Our overall objectives were to use MR images from children who were screened and/or participated in the Silent Cerebral Infarct Treatment in SCD (SIT) trial to 1) determine the burden of dPVS in children with SCD, specifically within the basal ganglia and centrum semiovale, and 2) correlate these findings with other markers of CSVD, specifically silent cerebral infarctions. Methods: The SIT trial was a multicenter, randomized clinical trial that evaluated the effect of monthly chronic transfusions to prevent the development of new SCI in children with SCD. As part of the enrollment process, all children underwent an initial MRI. We used both the Wardlaw (currently used as part of the international consensus criteria for evaluating CSVD) and Rotterdam criteria to quantify dPVS burden on T2-weighted screening MR images for 340 participants from the SIT trial. Briefly, both rating scales evaluate dPVS in the BG, CO, and midbrain (MB); the Rotterdam criteria also includes the hippocampus. The Wardlaw criteria categorize dPVS on an ordinal scale from 0 (none) to 4 (> 40) in the BG and CO and 0 or 1 point (absent or present) for the MB, with a total score of 9 as the maximum dPVS burden from all 3 brain regions. The Rotterdam criteria uses a semi-continuous scale and specifies counting dPVS to a total of 20 for each region for a maximum combined dPVD burden score of 80. Additional variables in our analysis were participant's age, hemoglobin, total white blood cell (WBC) count, and presence of SCI at baseline. We categorized dPVS burden score from the Wardlaw rating scale into low (0-2), medium (3-4), and high ( 5) and performed an ordinal multivariate logistic regression with age, sex, presence of SCI, hemoglobin, and total WBC count as independent variables. Results: We completed the two dPVS rating scales on 340 initial (screening) MR images from 340 children screened for the SIT trial, with a median age of 8.3 years (range 5 - 15 years). Eighty-eight (26%) had evidence of at least one SCI. The mean hemoglobin was 8 ± 1.1 g/dL and total WBC count was 12,000 ± 4200 cells/ml. The mean dPVS burden score from the Wardlaw criteria was 3.7 ± 1.7, while for the Rotterdam criteria, the mean was 32 ± 14 (Table). Global and regional dPVS scores from the two rating scales were well correlated (p < 0.001, r = 0.72 - 0.8). dPVS score in the BG and CSO was moderately correlated (p < 0.001, r = 0.45). There was no significant sex difference in dPVS burden (mean Wardlaw rating: males = 3.9 versus females = 3.6, p = 0.08). Multivariate analysis show that increasing age was associated with dPVS burden (p = 0.005), as was increasing hemoglobin, which showed a trend towards association (p = 0.06), potentially due to increased pressure within microvasculature, resulting in extravasation of fluid into the surrounding space. Surprisingly, presence or size of SCI were not associated with dPVS burden. Conclusions: Children with SCD have evidence of more than expected dilated perivascular spaces compared to not only healthy children but also adults, which increase with age. Although likely involved in neurological injury, dilated PVS in children with SCD do not appear to be associated with the presence of CSVD phenotypes such as SCI. We reasoned that in SCD, dPVS may be sequelae of underlying neuroinflammation. Future studies are needed to examine correlation of dPVS with biomarkers of neuroinflammation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anxiolytic, anti-nociceptive and body weight reducing effects of L-lysine in rats: Relationship with brain serotonin an In-Vivo and In-Silico study.

L-lysine (L-lys) had long been comprehended as an essential amino acid for humans. There were reports that the absence or inadequate availability of L-lys in the diet may lead to mental and physical impairments. The present study was designed to explore the effects of L-lys on body weight changes, cumulative food intake, anxiety-like behavior and pain perception in rats. 5-Hydroxytryptamine (5-HT, serotonin) metabolism, and tryptophan (Trp) levels in the midbrain (MB), hippocampus (HP), and prefrontal cortex (PFC) were also determined. Animals were treated with L-lys in doses of 0.5g/kg and 1g/kg for 20 days and behavioral studies were performed on day 1st and day 20th. After monitoring behaviors on day 20th, animals were killed to collect the serum and brain regions MB, HP and PFC. 5-HT metabolism and Trp levels were determined by HPLC-EC. The treatment produce no effect on food intakes but body weights were reduced. 20 days administration of L-lys produced an anxiolytic effect and increased exploratory activity on day 1st. Repeated administration of L-lys increased 5-HT levels in the PFC and HP. 5-Hydroxyindoleacetic acid (5-HIAA), the metabolite of 5-HT, decreased in the HP. Trp, the precourser of 5-HT, decreased in the PFC. Results suggested a decrease in 5-HT degredation in enhancing 5-HT levels. Results of in-silico analysis showed that lysine had a potential binding affinity for MAO (monoamine oxidase) A and B with an energy of (-4.8kcal/mol and -5.3kcal/mol) respectively. The molecular dynamic simulation study revealed the stability of L-lys after 10ns for each protein. Conclusively, the present study showed that L-lys produced an anxiolytic effect and reduced body weight. These beneficial effects were associated with an increase in 5-HT levels in the PFC and HP. In-silico analysis suggested that 5-HT increase were due to the binding of L-lys with MAOs resulting in an inhibition of the degradation of monoamine.

Tramadol and Codeine Stacking/Boosting Dose Exposure Induced Neurotoxic Behaviors, Oxidative Stress, Mitochondrial Dysfunction, and Neurotoxic Genes in Adolescent Mice

In spite of the increasing epidemic of pharmaceutical opioids (codeine and tramadol) misuse and abuse among the adolescents, little is known about the neurotoxic consequences of the widespread practice of tramadol and codeine abuse involving increasing multiple doses across days, referred to as stacking and boosting. Hence, in this study, we replicated stacking and boosting doses of tramadol, codeine alone, or in combination on spontaneous motor activity and cognitive function in adolescent mice and adduced a plausible mechanism of possible neurotoxicity. Ninety-six adolescent mice were randomly distributed into 4 groups (n = 24 per group) and treated thrice daily for 9days with vehicle, tramadol (20, 40, or 80mg/kg), codeine (40, 80, or 160mg/kg), or their combinations. Exposure of mice to tramadol induced hyperactivity and stereotypic behavior while codeine exposure caused hypoactivity and nootropic effect but tramadol-codeine cocktail led to marked reduction in spontaneous motor activity and cognitive function. In addition, tramadol, codeine, and their cocktail caused marked induction of nitroso-oxidative stress and inhibition of mitochondrial complex I activity in the prefrontal cortex (PFC) and midbrain (MB). Real-time PCR expression profiling of genes encoding neurotoxicity (RT) showed that tramadol exposure upregulate 57 and downregulate 16 neurotoxic genes, codeine upregulate 45 and downregulate 25 neurotoxic genes while tramadol-codeine cocktail upregulate 52 and downregulate 20 neurotoxic genes in the PFC. Findings from this study demonstrate that the exposure of adolescents mice to multiple and increasing doses of tramadol, codeine, or their cocktail lead to spontaneous motor coordination deficits indicative of neurotoxicity through induction of oxidative stress, inhibition of mitochondrial complex I activity and upregulation of neurotoxicity encoding genes in mice.

Biological effects of inhaled crude oil vapor V. Altered biogenic amine neurotransmitters and neural protein expression

Workers in the oil and gas industry are at risk for exposure to a number of physical and chemical hazards at the workplace. Chemical hazard risks include inhalation of crude oil or its volatile components. While several studies have investigated the neurotoxic effects of volatile hydrocarbons, in general, there is a paucity of studies assessing the neurotoxicity of crude oil vapor (COV). Consequent to the 2010 Deepwater Horizon (DWH) oil spill, there is growing concern about the short- and long-term health effects of exposure to COV. NIOSH surveys suggested that the DWH oil spill cleanup workers experienced neurological symptoms, including depression and mood disorders, but the health effects apart from oil dispersants were difficult to discern. To investigate the potential neurological risks of COV, male Sprague-Dawley rats were exposed by whole-body inhalation to COV (300 ppm; Macondo surrogate crude oil) following an acute (6 h/d × 1 d) or sub-chronic (6 h/d × 4 d/wk. × 4 wks) exposure regimen. At 1, 28 or 90 d post-exposure, norepinephrine (NE), epinephrine (EPI), dopamine (DA) and serotonin (5-HT) were evaluated as neurotransmitter imbalances are associated with psychosocial-, motor- and cognitive- disorders. Sub-chronic COV exposure caused significant reductions in NE, EPI and DA in the dopaminergic brain regions, striatum (STR) and midbrain (MB), and a large increase in 5-HT in the STR. Further, sub-chronic exposure to COV caused upregulation of synaptic and Parkinson's disease-related proteins in the STR and MB. Whether such effects will lead to neurodegenerative outcomes remain to be investigated.