Corpus callosum and cerebellum participate in semantic dysfunction of Parkinson's disease: a diffusion tensor imaging-based cross-sectional study.

Language dysfunction is common in Parkinson's disease (PD) patients, among which, the decline of semantic fluency is usually observed. This study aims to explore the relationship between white matter (WM) alterations and semantic fluency changes in PD patients. 127 PD patients from the Parkinson's Progression Markers Initiative cohort who received diffusion tensor imaging scanning, clinical assessment and semantic fluency test (SFT) were included. Tract-based special statistics, automated fiber quantification, graph-theoretical and network-based analyses were performed to analyze the correlation between WM structural changes, brain network features and semantic fluency in PD patients. Fractional anisotropy of corpus callosum, anterior thalamic radiation, inferior front-occipital fasciculus, and uncinate fasciculus, were positively correlated with SFT scores, while a negative correlation was identified between radial diffusion of the corpus callosum, inferior longitudinal fasciculus, and SFT scores. Automatic fiber quantification identified similar alterations with more details in these WM tracts. Brain network analysis positively correlated SFT scores with nodal efficiency of cerebellar lobule VIII, and nodal local efficiency of cerebellar lobule X. WM integrity and myelin integrity in the corpus callosum and several other language-related WM tracts may influence the semantic function in PD patients. Damage to the cerebellum lobule VIII and lobule X may also be involved in semantic dysfunction in PD patients.

Cerebellar and cerebral white matter changes in Parkinson's disease with resting tremor.

PURPOSE: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI). METHODS: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed. RESULTS: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR. CONCLUSION: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD.

Epileptiform Discharges Reduce Neuronal ATP Production by Inhibiting F0F1-ATP Synthase Activity via A Zinc-α2-Glycoprotein-Dependent Mechanism.

Neuronal energy metabolism dysfunction, especially adenosine triphosphate (ATP) supply decrease, is observed in epilepsy and associated with epileptogenesis and prognosis. Zinc-α2-glycoprotein (ZAG) is known as an important modulator of energy metabolism and involved in neuronal glucose metabolism, fatty acid metabolism, and ketogenesis impairment in seizures, but its effect on neuronal ATP synthesis in seizures and the specific mechanism are unclear. In this study, we verified the localization of ZAG in primary cultured neuronal mitochondria by using double-labeling immunofluorescence, immune electron microscopy, and western blot. ZAG level in neuronal mitochondria was modulated by lentiviruses and detected by western blot. The F0F1-ATP synthase activity, ATP level, and acetyl-CoA level were measured. The binding between ZAG and F0F1-ATP synthase was determined by coimmunoprecipitation. We found that both ZAG and F0F1-ATP synthase existed in neuronal mitochondria, and there was mutual binding between them. Epileptiform discharge-induced decrease of mitochondrial ZAG level was reversed by ZAG overexpression. Epileptiform discharge or ZAG knockdown decreased F0F1-ATP synthase activity and ATP level in neurons, which were reversed by ZAG overexpression, while overexpression of ZAG along only increased F0F1-ATP synthase activity but not increased ATP level. Meanwhile, neither epileptiform discharges nor changes of ZAG level can alter the acetyl-CoA level. Moreover, epileptiform discharge did not alter F0F1-ATP synthase level. In conclusion, epileptiform discharge-induced ZAG decrease in neuronal mitochondria is correlated to F0F1-ATP synthase activity inhibition, which may possibly lead to ATP supply impairments. ZAG may be a potential therapeutic target for treating neuronal energy metabolism dysfunction in seizures with further researches.

Collagen changes in rabbit conjunctiva after conjunctival crosslinking.

This study aims to determine the ultrastructural changes in collagen fibrils in rabbit conjunctiva after conjunctival crosslinking using riboflavin and ultraviolet A (UVA) light at an irradiation intensity of 45 mW/cm2. Conjunctival crosslinking may increase conjunctival stiffness. The supertemporal quadrants of the right eyes of 24 adult rabbits were treated with a topical riboflavin solution (0.25%) before irradiation with UVA light at 45 mW/cm2 for 4 min. After 3 weeks, the collagen fibrils in fibril bundles were examined by electron microscopy. Immunohistochemical staining was used to detect the expression levels of collagen I and collagen III in the rabbits' conjunctiva. The diameter of the collagen fibrils in the fibril bundles varied slightly, ranging from 30 to 60 nm in the conjunctival stroma of the control group. In the treatment group, the diameter of collagen fibrils ranged from 60 to 90 nm. The thickest collagen fibrils were observed in the treatment group (up to 90 nm in diameter). In contrast, those in the conjunctival stroma of the control group were considerably smaller (up to 60 nm in diameter). However, thicknesses of collagen fibrils displayed a unimodal distribution. Both collagen I and collagen III increased after treatment with riboflavin and UVA light irradiation at 45 mW/cm2. The data indicate that in rabbits, conjunctival crosslinking with riboflavin and UVA light at 45 mW/cm2 for 4 min is safe and does not induce ultrastructural alterations of the conjunctival cells. The conjunctival crosslinking with riboflavin and UVA light at 45 mW/cm2 can increase the diameter of collagen fibrils, but the average densities of collagen I and collagen III have no statistical significance.

Glucose metabolism impairment in Parkinson's disease.

Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are associated with the incidence, progression, and special phenotypes of PD, which affect each physiological process of glucose metabolism including glucose uptake, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate shunt pathway. These impairments may be attributed to various mechanisms, such as insulin resistance, oxidative stress, abnormal glycated modification, blood-brain-barrier dysfunction, and hyperglycemia-induced damages. These mechanisms could subsequently cause excessive methylglyoxal and reactive oxygen species production, neuroinflammation, abnormal aggregation of protein, mitochondrial dysfunction, and decreased dopamine, and finally result in energy supply insufficiency, neurotransmitter dysregulation, aggregation and phosphorylation of α-synuclein, and dopaminergic neuron loss. This review discusses the glucose metabolism impairment in PD and its pathophysiological mechanisms, and briefly summarized the currently-available therapies targeting glucose metabolism impairment in PD, including glucagon-likepeptide-1 (GLP-1) receptor agonists and dual GLP-1/gastric inhibitory peptide receptor agonists, metformin, and thiazoledinediones.

Risk factors related to early neurological deterioration in lacunar stroke and its influence on functional outcome.

OBJECTIVE: To identify risk factors for early neurological deterioration (END) in acute lacunar stroke patients and its influence on functional outcome. METHODS: Consecutive acute lacunar stroke patients defined by magnetic resonance imaging (MRI) between January 2018 and June 2020 were included in the study. END was defined as any persisting increase in National Institutes of Health Stroke Scale (NIHSS) score of ⩾ 2 points post admission, and favorable outcome was defined as a modified Rankin Scale (mRS) of 0-2 at discharge. Univariable and multivariable logistic regression were performed to identify risk factors related to END, as well as the influence of END on functional outcome. RESULTS: Among a total of 638 lacunar stroke patients (420 males (65.8%), median age 66 years (interquartile range (IQR): 56-74)), 108 (16.9%) developed END, and 94.4% (102/108) of the END occurred within 72 h post admission. Admission NIHSS score (adjusted odds ratio (aOR) 1.132, 95% confidence interval (CI) 1.046-1.225, p = 0.002), female (aOR 2.752, 95% CI 1.277-5.933, p = 0.010), admission systolic blood pressure (SBP) (160-179 mm Hg) (aOR 9.395, 95% CI 4.310-20.479, p < 0.001) and admission SBP (⩾180 mm Hg) (aOR 16.030, 95% CI 5.991-42.891, p < 0.001) were significantly associated with END. Delay time from onset to admission (aOR 0.995, 95% CI 0.990-1.000, p = 0.031), SBP dropping (⩾20 mm Hg) within 3 days or when END occurred (aOR 0.037, 95% CI 0.016-0.086, p < 0.001) and thalamic lacunar infarction (aOR 0.098, 95% CI 0.012-0.827, p = 0.033) were inversely associated with END. END (aOR 12.374, 95% CI 6.881-22.254, p < 0.001) and higher admission NIHSS score (aOR 1.488, 95% CI 1.359-1.629, p < 0.001) predicted unfavorable outcome at discharge. CONCLUSION: END in lacunar stroke patients is common and is associated with unfavorable outcome. Admission high SBP is a potentially modifiable risk factor for prevention of END, but this needs further investigation.

Levodopa responsiveness and white matter alterations in Parkinson's disease: A DTI-based study and brain network analysis: A cross-sectional study.

BACKGROUND: Patients with Parkinson's disease (PD) present various responsiveness to levodopa, but the cause of such differences in levodopa responsiveness is unclear. Previous studies related the damage of brain white matter (WM) to levodopa responsiveness in PD patients, but no study investigated the relationship between the structural brain network change in PD patients and their levodopa responsiveness. METHODS: PD patients were recruited and evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Each patient received a diffusion tensor imaging (DTI) scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated. PD patients were grouped into irresponsive group (improvement rate < 30%) and responsive group (improvement rate ≥ 30%). Tract-based spatial statistics (TBSS), deterministic tracing (DT), region of interest (ROI) analysis, and automatic fiber identification (AFQ) analyses were performed. The structural brain network was also constructed and the topological parameters were calculated. RESULTS: Fifty-four PD patients were included. TBSS identified significant differences in fractional anisotropy (FA) values in the corpus callosum and other regions of the brain. DT and ROI analysis of the corpus callosum found a significant difference in FA between the two groups. Graph theory analysis showed statistical differences in global efficiency, local efficiency, and characteristic path length. CONCLUSION: PD patients with poor responsiveness to levodopa had WM damage in multiple brain areas, especially the corpus callosum, which might cause disruption of information integration of the structural brain network.

Effects of Anti-Parkinsonian Drugs on Verbal Fluency in Patients with Parkinson's Disease: A Network Meta-Analysis.

Verbal fluency impairment is common in patients with Parkinson's disease (PD), but the effect of drugs on verbal fluency in PD patients has not been comprehensively evaluated. We conducted a network meta-analysis based on four online databases to compare the effect of drugs on verbal fluency in PD patients. This study was performed and reported according to PRISMA-NMA guidelines. In total, 6 out of 3707 articles (three RCTS and three cross-sectional studies) covering eight drug regimens were included (five for letter fluency, five for semantic fluency). In terms of letter fluency, the ranking of the overall efficacy of included drug regimens was: levodopa, levodopa combined with pramipexole, rotigotine, cabergoline, pramipexole, pergolide, but no drug regimen presented a significant advantage over the others. In terms of semantic fluency, the ranking of the overall efficacy of included drug regimens was: rotigotine, levodopa, cabergoline, pergolide, pramipexole, among which, levodopa alone (SMD = 0.93, 95%CI: 0.28-1.59) and rotigotine alone (SMD = 1.18, 95%CI: 0.28-2.09) were statistically superior to pramipexole, while no significant difference was identified between all the other drug regimens. Levodopa and rotigotine seem to be more appropriate choices for PD patients with verbal fluency impairment. Further study is needed to illustrate the efficacy of drugs on verbal fluency in PD patients.

A review on pathology, mechanism, and therapy for cerebellum and tremor in Parkinson's disease.

Tremor is one of the core symptoms of Parkinson's disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

Characterization of plant growth-promoting traits of Enterobacter sp. and its ability to promote cadmium/lead accumulation in Centella asiatica L.

In the present study, we characterized the plant growth-promoting traits of Enterobacter sp. FM-1 (FM-1) and investigated its ability to promote growth and increase IAA, P, and Fe concentrations as well as Cd and Pb accumulation in Centella asiatica L. (C. asiatica L.) in upstream area (UA) soil and downstream area (DA) soil that we collected from Siding mine. The results demonstrated that FM-1 secreted IAA, produced siderophores, and had P-solubilization ability even under Cd exposure. IAA secretion reached a maximum of 108.3 ± 1.3 mg L-1 under Cd exposure at 25 mg L-1. Siderophore production reached a maximum of 0.94 ± 0.01 under Cd exposure at 50 mg L-1. Pot experiments indicated that FM-1 successfully colonized the roots of C. asiatica L. In both soils, inoculation with FM-1 decreased the pH in rhizosphere soil and increased the bioavailability of both Cd and Pb. In addition, inoculation with FM-1 increased the IAA, P, and Fe concentrations and simultaneously promoted both Cd and Pb accumulation in C. asiatica L. The Cd and Pb concentrations in leaves increased 1.73- and 1.07-fold in the UA soil and 1.25- and 1.11-fold in the DA soil, respectively. Thus, the Cd-resistant strain FM-1 presented excellent PGP traits and could facilitate Cd and Pb phytoremediation by C. asiatica L.

Diffusion-weighted imaging lesions after endovascular treatment of cerebral aneurysms: A network meta-analysis.

Background: Thromboembolism is one of the common complications in endovascular treatments including coiling alone, stent-assisted coiling (SAC), balloon-assisted coiling (BAC), and flow-diverting (FD) stents. Such treatments are widely used in intracranial aneurysms (IAs), which usually present as positive lesions in diffusion-weighted imaging (DWI). Whether these adjunctive techniques increase postprocedural DWI-positive lesions after endovascular treatment remains unclear. Methods: A thorough electronic search for the literature published in English between January 2000 and October 2022 was conducted on PubMed, Medline, and EMBASE. Eighteen studies (3 cohort studies and 15 case-control studies) involving 1,843 patients with unruptured IAs (UIAs) were included. We performed a frequentist framework network meta-analysis (NMA) to compare the rank risks of cerebral thromboembolism of the above four endovascular treatments. The incoherence test was used to analyze the statistical disagreement between direct and indirect evidence. Funnel plots were used to analyze publication bias. Results: The incidences of DWI lesions in patients who received FD stents, SAC, BAC, and coiling alone were 66.1% (109/165), 37.6% (299/795), 31.1% (236/759), and 25.6% (236/921). The incidence of DWI lesions in patients who received FD stents was higher than that in patients who received SAC [OR: 2.40; 95% CI (1.15, 5.00), P < 0.05], BAC [OR: 2.62; 95% CI (1.19, 5.77), P < 0.05], or coiling alone [OR: 2.77; 95% CI (1.26, 6.07), P < 0.05]. The incoherence test showed preferable consistency in this NMA. No obvious publication bias was found in the funnel plot. Conclusion: FD stent placement brings more ischemic lesions identified by DWI than any other procedures for patients with UIA. The characteristics of FD stents may result in a high incidence of DWI lesions.

Fyn kinase regulates dopaminergic neuronal apoptosis in animal and cell models of high glucose (HG) treatment.

BACKGROUND: High glucose (HG) is linked to dopaminergic neuron loss and related Parkinson's disease (PD), but the mechanism is unclear. RESULTS: Rats and differentiated SH-SY5Y cells were used to investigate the effect of HG on dopaminergic neuronal apoptotic death. We found that a 40-day HG diet elevated cleaved caspase 3 levels and activated Fyn and mTOR/S6K signaling in the substantia nigra of rats. In vitro, 6 days of HG treatment activated Fyn, enhanced binding between Fyn and mTOR, activated mTOR/S6K signaling, and induced neuronal apoptotic death. The proapoptotic effect of HG was rescued by either the Fyn inhibitor PP1 or the mTOR inhibitor rapamycin. PP1 inhibited mTOR/S6K signaling, but rapamycin was unable to modulate Fyn activation. CONCLUSIONS: HG induces dopaminergic neuronal apoptotic death via the Fyn/mTOR/S6K pathway.

The Efficacy and Safety of Pharmacological Treatments for Restless Legs Syndrome: Systemic Review and Network Meta-Analysis.

Although various drugs are currently used for restless legs syndrome (RLS) in clinic, selecting appropriate drugs for patients is difficult. This network meta-analysis (NMA) aimed to compare the efficacy and safety of different drugs. After literature searching and screening, 46 trials, including 10,674 participants are included in this NMA. The pooled results showed that, compared with placebo, only levodopa is inefficient to relieve symptoms of RLS. Cabergoline decreases IRLS scores to the greatest extent among all drugs (MD -11.98, 95% CI -16.19 to -7.78). Additionally, pramipexole is superior to ropinirole in alleviating symptoms of RLS (MD -2.52, 95% CI -4.69 to -0.35). Moreover, iron supplement alleviates RLS symptoms significantly compared with placebo in patient with iron deficiency (MD -5.15, 95% CI -8.99 to -1.31), but not for RLS patients with normal serum ferritin level (MD -2.22, 95% CI -6.99 to 2.56). For primary RLS, these drugs are also effective, while there is insufficient data to analyze drug efficacy in secondary RLS. We analyzed risk of common adverse effects of drugs including nausea, somnolence, fatigue, headache and nasopharyngitis. Alpha-2-delta ligands and DAs are favorable choices for both primary and secondary RLS because of their significant efficacy and good tolerability. Iron supplement can significantly alleviate symptoms of RLS patients with iron deficiency than placebo. We recommend gabapentin, gabapentin enacarbil, and pregabalin for clinicians for first consideration mainly because that they rarely cause augmentation. Oxycodone-naloxone could be considered in patients with severe or very severe RLS who failed in treatment with above drugs.

Glucose transporter 3 in neuronal glucose metabolism: Health and diseases.

Neurons obtain glucose from extracellular environment for energy production mainly depending on glucose transporter 3 (GLUT3). GLUT3 uptakes glucose with high affinity and great transport capacity, and is important for neuronal energy metabolism. This review summarized the role of neuronal GLUT3 in brain metabolism, function and development under both physiological conditions and in diseases, aiming to provide insights into neuronal glucose metabolism and its effect on brain. GLUT3 stabilizes neuronal glucose uptake and utilization, influences brain development and function, and ameliorates aging-related manifestations. Neuronal GLUT3 is regulated by synaptic activity, hormones, nutrition, insulin and insulin-like growth factor 1 in physiological conditions, and is also upregulated by hypoxia-ischemia. GLUT3-related neuronal glucose and energy metabolism is possibly involved in the pathogenesis, pathophysiological mechanism, progression or prognosis of brain diseases, including Alzheimer's disease, Huntington's disease, attention-deficit/hyperactivity disorder and epilepsy. GLUT3 may be a promising therapeutic target of these diseases. This review also briefly discussed the role of other glucose transporters in neuronal glucose metabolism, which work together with GLUT3 to sustain and stabilize glucose and energy supply for neurons. Deficiency in these glucose transporters may also participate in brain diseases, especially GLUT1 and GLUT4.

Levodopa responsiveness in Parkinson's disease patients and white matter alterations in diffusion tensor imaging: a cross-sectional tract-based spatial statistics study.

This study aimed to investigate the relationship between levodopa responsiveness and white matter alterations in Parkinson's disease patients using diffusion tensor imaging (DTI). Twenty-six recruited Parkinson's disease patients were evaluated using the Mini-Mental State Examination, Hoehn and Yahr scale (H&Y) and Unified Parkinson's Disease Rating Scale (UPDRS). Each patient underwent a DTI scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated, Parkinson's disease patients were grouped into a responsive group (improvement rate ≥30%) and a nonresponsive group (improvement rate <30%). The differences in fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity between the two groups were measured using tract-based spatial statistics. There was no difference in demographic features or baseline evaluations between groups. The UPDRS-III score after the challenge was higher in the nonresponsive group than that in the responsive group. Compared to the responsive group, patients in the nonresponsive group exhibited decreased fractional anisotropy in the corpus callosum; cingulum; left corona radiata; left internal capsule; left middle frontal gyrus; left superior longitudinal fasciculus and right somatosensory cortex. Mean diffusivity and radial diffusivity were increased in wide-ranging areas in the nonresponsive group. No difference was observed in axial diffusivity. White matter alterations in the abovementioned areas may affect the function of the dopaminergic network and thus may be associated with the levodopa response in Parkinson's disease patients. Further studies are needed to analyze the specific mechanism and pathological changes underlying these effects.

Plasma C-Reactive Protein Level and Outcome of Acute Ischemic Stroke Patients Treated by Intravenous Thrombolysis: A Systematic Review and Meta-Analysis.

INTRODUCTION: The plasma C-reactive protein (CRP) level in predicting prognosis of acute ischemic stroke (AIS) patients receiving intravenous thrombolysis (IVT) is not yet established. This study is aiming to investigate the relationship between the plasma CRP level and outcome of AIS patients receiving IVT. METHODS: PubMed and EMBASE were searched for relevant studies that evaluated the relationship between the CRP level and outcome of AIS patients receiving IVT. STATA 12.0 was used to pool the data for meta-analysis. RESULTS: In total, 8 studies were included. Six studies reported a positive relationship between the high CRP level and unfavorable outcome at 3 months. Five studies associated the high plasma CRP level with high mortality at 3 months. And meta-analysis further confirmed that the high CRP level was related to unfavorable outcomes (odds ratio [OR] = 1.716, 95% CI: 1.170-2.517, p = 0.006) and mortality (OR = 2.751, 95% CI: 1.613-4.693, p < 0.001) at 3 months. However, an elevated CRP level was not found to increase the risk of symptomatic intracerebral hemorrhage. CONCLUSION: A high plasma CRP level was associated with a 3-month poor outcome of AIS patients treated with IVT. CRP may be used as a biomarker for the risk stratification of AIS patients as candidates receiving IVT or other alternative therapy such as mechanical thrombectomy.

Zinc-α2-glycoprotein relieved seizure-Induced neuronal glucose uptake impairment via insulin-like growth factor 1 receptor-regulated glucose transporter 3 expression.

Glucose hypometabolism is observed in epilepsy and promotes epileptogenesis. Glucose hypometabolism in epilepsy may be attributed to decreased neuronal glucose uptake, but its molecular mechanism remains unclear. Zinc-α2-glycoprotein (ZAG) is related to glucose metabolism and is reported to suppress seizures. The anti-epileptic effect of ZAG may be attributed to its regulation of neuronal glucose metabolism. This study explored the effect of ZAG on neuronal glucose uptake and its molecular mechanism via insulin-like growth factor 1 receptor (IGF1R)-regulated glucose transporter 3 (GLUT-3) expression. The ZAG level was modulated by lentivirus in primary culture neurons. Neuronal seizure models were induced by Mg2+ -free artificial cerebrospinal fluid. We assessed neuronal glucose uptake by the 2-NBDG method and Glucose Uptake Colorimetric Assay Kit. IGF1R was activated by IGF1 and blocked by AXL1717. The expression and distribution of IGF1R and GLUT-3, together with IGF1R phosphorylation, were measured by western blot. The binding between ZAG and IGF1R was determined by coimmunoprecipitation. Neuronal glucose uptake and GLUT-3 expression were significantly decreased by seizure or ZAG knockdown, whereas ZAG over-expression or IGF1 treatment reversed this decrease. The effect of ZAG on neuronal glucose uptake and GLUT-3 expression was blocked by AXL1717. ZAG increased IGF1R distribution and phosphorylation possibly by binding. Additionally, IGF1R increased GLUT-3 activity by increasing GLUT-3 expression. In epilepsy/seizure, neuronal glucose uptake suppression may be attributed to a decrease in ZAG, which suppresses neuronal GLUT-3 expression by regulating the activity of IGF1R. ZAG, IGF1R, and GLUT-3 may be novel potential therapeutic targets of glucose hypometabolism in epilepsy and seizures.

Parkinson's Disease-Related Risk of Suicide and Effect of Deep Brain Stimulation: Meta-Analysis.

BACKGROUND: Previous studies investigated the risk of suicide in patients with Parkinson's disease (PD) but reported discrepant results. Deep brain stimulation (DBS) is an effective therapy for PD, while its effect on suicide risk has seldom been researched. This meta-analysis aimed to estimate the risk of suicide and/or suicidal ideation in PD patients and in PD patients who underwent DBS. METHODS: Relevant articles published in the PubMed or EMBASE or CNKI database from 1990 to December 2019 were sourced, and the combined standardized mortality rate (SMR) or odds ratio (OR) was pooled. RESULT: A total of 1070 articles were found. After screening, 4 cross-sectional studies, 4 cohort studies, 2 randomized controlled trial studies, and 2 case-control studies were included in this meta-analysis. Pooled data indicated that PD patients may have increased risk of suicide (lnSMR, 0.459; 95% confidence interval (CI), 0.286 to 0.632; p < 0.001). No significant difference was found in the risk of suicide when comparing PD patients who underwent DBS with PD patients who received only drug therapy (OR = 2.844, 95%CI: 0.619 to 13.072, p=0.179). DBS may increase the risk of suicide and/or suicidal ideation in PD patients compared with general population (lnSMR = 3.383, 95%CI: 2.839 to 3.927, p < 0.001). CONCLUSION: PD patients have higher risk of suicide and/or suicidal ideation compared with controls, while PD patients who received DBS tend to have an increased risk of suicide or suicidal ideation. Psychological evaluation is needed in PD patients, and pre- and post-operation evaluations are necessary for PD patients who underwent DBS.

Seizure-induced impairment in neuronal ketogenesis: Role of zinc-α2-glycoprotein in mitochondria.

Ketone bodies (KBs) were known to suppress seizure. Untraditionally, neurons were recently reported to utilize fatty acids and produce KBs, but the effect of seizure on neuronal ketogenesis has not been researched. Zinc-α2-glycoprotein (ZAG) was reported to suppress seizure via unclear mechanism. Interestingly, ZAG was involved in fatty acid ß-oxidation and thus may exert anti-epileptic effect by promoting ketogenesis. However, this promotive effect of ZAG on neuronal ketogenesis has not been clarified. In this study, we performed immunoprecipitation and mass spectrometry to identify potential interaction partners with ZAG. The mechanisms of how ZAG translocated into mitochondria were determined by quantitative coimmunoprecipitation after treatment with apoptozole, a heat shock cognate protein 70 (HSC70) inhibitor. ZAG level was modulated by lentivirus in neurons or adeno-associated virus in rat brains. Seizure models were induced by magnesium (Mg2+ )-free artificial cerebrospinal fluid in neurons or intraperitoneal injection of pentylenetetrazole kindling in rats. Ketogenesis was determined by cyclic thio-NADH method in supernatant of neurons or brain homogenate. The effect of peroxisome proliferator-activated receptor γ (PPARγ) on ZAG expression was examined by Western blot, quantitative real-time polymerase chain reaction (qRT-PCR) and chromatin immunoprecipitation qRT-PCR. We found that seizure induced ketogenesis deficiency via a ZAG-dependent mechanism. ZAG entered mitochondria through a HSC70-dependent mechanism, promoted ketogenesis by binding to four ß-subunits of long-chain L-3-hydroxyacyl-CoA dehydrogenase (HADHB) and alleviated ketogenesis impairment in a neuronal seizure model and pentylenetetrazole-kindled epileptic rats. Additionally, PPARγ activation up-regulated ZAG expression by binding to promoter region of AZGP1 gene and promoted ketogenesis through a ZAG-dependent mechanism.