Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin's effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson's disease (PD). Western blot analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt in MN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNA knockdown of PKD1 blocked the activation of Akt, suggesting that PKD1 acts as an upstream regulator of Akt in quercetin-mediated neuroprotective signaling. Quercetin also enhanced cAMP response-element binding protein phosphorylation and expression of the cAMP response-element binding protein target gene brain-derived neurotrophic factor. Results from qRT-PCR, Western blot analysis, mtDNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN9D cells against 6-hydroxydopamine-induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlying PD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model of PD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, and TH neuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates the PKD1-Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14033

Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.

https://www.mdpi.com/2218-273X/10/5/687/pdf

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment

Nicotinamide (NAM) is a form of vitamin B3 that, when administered at near-gram doses, has been shown or suggested to be therapeutically effective against many diseases and conditions. The target conditions are incredibly diverse ranging from skin disorders such as bullous pemphigoid to schizophrenia and depression and even AIDS. Similar diversity is expected for the underlying mechanisms. In a large portion of the conditions, NAM conversion to nicotinamide adenine dinucleotide (NAD+) may be a major factor in its efficacy. The augmentation of cellular NAD+ level not only modulates mitochondrial production of ATP and superoxide, but also activates many enzymes. Activated sirtuin proteins, a family of NAD+-dependent deacetylases, play important roles in many of NAM’s effects such as an increase in mitochondrial quality and cell viability countering neuronal damages and metabolic diseases. Meanwhile, certain observed effects are mediated by NAM itself. However, our understanding on the mechanisms of NAM’s effects is limited to those involving certain key proteins and may even be inaccurate in some proposed cases. This review details the conditions that NAM has been shown to or is expected to effectively treat in humans and animals and evaluates the proposed underlying molecular mechanisms, with the intention of promoting wider, safe therapeutic application of NAM. NAM, by itself or through altering metabolic balance of NAD+ and tryptophan, modulates mitochondrial function and activities of many molecules and thereby positively affects cell viability and metabolic functions. And, NAM administration appears to be quite safe with limited possibility of side effects which are related to NAM’s metabolites.

Diverse therapeutic efficacies and more diverse mechanisms of nicotinamide.

The posterior inferior cerebellar artery (PICA), with its unique anatomical complexity, is of great clinical importance and involved in many diseases including aneurysm, ischemic stroke, neurovascular compression syndrome (NVCS), arteriovenous malformation (AVM), and brain tumor. However, a comprehensive systematic review of the importance of the PICA is currently lacking. In this study, we perform a literature review of PICA by searching all the associated papers in the PUBMED database hoping to provide a better understanding of the artery. The PICA has tortuous and variable course and territory, divided into 5 segments. Various aneurysms involving PICA were not uncommon, of which the treatment is challenging. The PICA infarct typically manifests lateral medullary syndrome (LMS) and is more likely to cause mass effects. The PICA frequently compresses the medulla and the cranial nerves resulting in various neurovascular compression syndromes (NVCS). Arteriovenous malformation (AVM) fed by PICA are associated with aneurysm and dissection which have high risk of rupture and worse outcome. PICA injured by head trauma can cause fatal SAH. VA terminating in PICA probably cause Bow hunter's syndrome (BHS). The PICA supplies many brain tumors and can be used in intracerebellar chemotherapy. The PICA can be exposed and injured during surgeries especially in telovelar approach, and it also plays an important role in bypass surgeries, hinting the surgical importance of PICA. In conclusion, PICA is very important in clinical practice.

/pdf/clinical-importance-of-the-posterior-inferior-cerebellar-26jgg3lnjo.pdf

Clinical Importance of the Posterior Inferior Cerebellar Artery: A Review of the Literature.

A review on recent trends in the phosphoproteomics workflow. From sample preparation to data analysis

Objective: To examine the protective effect of nicotinamide on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson′s disease(PD) in mouse model and its mechanisms.Methods: Parkinson′s disease was induced by injection of MPTP in adult male C57BL/6 mice,nicotinamide(500 mg/kg,i.p.) was given prior to subacute(30 mg/kg/d×5 d,i.p.) MPTP administration.Locomotor activities,striatal dopamine levels,lactate dehydrogenase(LDH) and NO synthase(NOS) activities of whole brains and striatum were analyzed at d5 after last MPTP injections.Results: Pretreatment with nicotinamide significantly improved the locomotor activity in the open-field test(P0.01),but not in the swimming test and grip climbing test.Nicotinamide administration resulted in sparing striatal dopamine levels from MPTP-induced dopamine depletion.There was no significant difference in LDH and NOS activities in the whole brains among the groups;but the activities in the striatum were drastically elevated after MPTP treatment.Nicotinamide pretreatment markedly inhibited MPTP-induced LDH and NOS activities(P0.01) and showed no significant difference compared to controls(P0.05).Conclusion: Nicotinamide protects dopaminergic neurons against MPTP-induced neurodegeneration,which suggests that the neuroprotective effects be associated with the inhibition of cell injuries and NOS activities.

[Protective effect of nicotinamide in a mouse Parkinson's disease model].

The aim of this study was to evaluate the feasibility of endovascular treatment (EVT) for ruptured very small (≤5 mm) or tiny (≤3 mm) paraclinoid aneurysms of the internal carotid artery (ICA). From November 2009 to April 2012, 32 ruptured paraclinoid aneurysms (very small, 23; tiny, 9) in 31 patients received EVT. Angiographic follow-up determined occlusion rates which were classified as total/near-total (95–100 %), subtotal (80–95 %), and partial (<80 %) occlusions. Follow-up data were retrospectively analyzed and categorized using the Modified Rankin Scale (mRS). Based on our paraclinoid aneurysm classification, 25 % (8) were classified as type I, 46.9 % (15) as type II, and 28.1 % (9) as type III. EVT was technically successful in 96.8 % (31), with coiling only in 12.5 % (4), balloon remolding coiling in 6.3 % (2), and stent-assisted coiling in 78.1 % (25). Total/near-total occlusion was immediately achieved in 34.4 % (11), subtotal occlusion in 37.5 % (12), and partial occlusion in 28.1 % (9). Follow-up angiography (mean, 9.9 ± 6.4 months) revealed total/near-total occlusion in 50 % (16) aneurysms, subtotal in 31.3 % (10), and partial occlusion in 18.8 % (6). At the end of clinical follow-up (mean, 14.8 ± 9.5 months), it revealed an mRS grade 0 in 38.7 % (12) of patients, grade 1 in 25.8 % (8), grade 2 in 22.6 % (7), grade 3 in 6.5 % (2), grade 4 in 3.2 % (1), and grade 5 in 3.2 % (1). EVT is feasible and effective for ruptured very small or tiny paraclinoid aneurysms of the ICA.

The feasibility and efficacy of endovascular treatment for very small or tiny ruptured paraclinoid aneurysms

Endovascular management of ruptured distal posterior inferior cerebellar artery aneurysms: A retrospective cohort study

Multiple spinal extradural arachnoid cysts (SEACs) are relatively rare lesions, which may cause symptoms due to spinal cord compression. Radical resection of multiple SEACs during one-stage surgery is the primary treatment for the rare lesion, because of its effective and safe operation. Here, we present a 13-year-old female, who presented with a 3-month history of progressive weakness in the right leg. For the first time, we reported partial resection of multiple SEACs without treating the other parts, can also lead to a favorable outcome. No change in the cysts and spinal deformity were observed during a follow-up period of 5 years.

/pdf/should-we-resect-all-multiple-intraspinal-extradural-23gdwe55mw.pdf

Should we resect all multiple intraspinal extradural arachnoid cysts? A case report.

OBJECTIVE: To evaluate the early management of intracranial ruptured vertebral dissecting aneurysms. METHODS: Twenty-two patients with ruptured vertebral dissecting aneurysms were managed by various treatment modalities according to their conditions. One aneurysm was treated by proximal vertebral artery coiling, 15 aneurysms by aneurysm and parent artery coiling, and 5 aneurysms by stent-assisted coiling (4 of 5 by stent-within-a-stent technique), one by single double-stent. Bloody cerebrospinal fluid was drained by postoperative lumbar subarachnoid drainage in order to prevent cerebral vasospasm. RESULTS: All 22 cases were successful without bleeding complication during the operation.There was 1 case of early postoperative non-aneurysmal hemorrhage, 2 cases of posterial group cranial nerves palsies, 1 case harbored Hunt & Hess IV who gave up treatment. After follow-up for 3-18 months, there was no rebleeding and infarction. Twenty patients recovered well, except 1 having posterial group cranial nerves palsies. Fourteen cases were followed up by angiography. In 3 patients treated by stent-assisted coiling, DSA showed that aneurysms disappeared and loading vessel passed freely.DSA of 11 cases with aneurysm and parent artery coiling demonstrated complete obliteration of the dissection without aneurysm imaging. CONCLUSION: Early endovascular treatment of ruptured vertebral dissecting aneurysms is essential. The selective method of endovascular management according to the characteristics of aneurysm is safe and effective. Double stent-assisted coiling should be the first choice.

Early management of intracranial ruptured vertebral dissecting aneurysms

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