Application of cinnarizine in migraine prevention: A systematic review and meta-analysis.

OBJECTIVE: To investigate and analyze the available data on the prophylactic effectiveness of cinnarizine in migraine disorder. BACKGROUND: Cinnarizine has demonstrated encouraging potential in preventing the attacks of migraine. Therefore, we opted to evaluate whether its sole administration leads to positive outcomes. METHODS: The PubMed, Scopus, Web of Science, and Embase databases were searched for English-only original interventional studies published until April 2022, then screened for relevancy and eligibility. The resulting data from the included studies, including the primary (ie, headache episode frequency, intensity, duration, monthly timing, and analgesic intake frequency) and secondary (ie, reported adverse events, quality of life, and activities of daily living) outcome changes compared to placebo and active controls (e.g., sodium valproate and propranolol) were then recorded by two independent assessors. Ultimately, these data were synthesized qualitatively and quantitatively (achieved by determining the mean difference via the random-effects model). RESULTS: A total of 10 studies comprising seven randomized controlled trials and three quasi-experimental studies were included. Compared to placebo, cinnarizine demonstrated significant improvements in migraine episode frequency (Mean difference = -3.10; Confidence interval = [-3.33, -2.88]; p-value < 0.001; I2  < 0.001%), and intensity (Mean difference = -1.54; Confidence interval = [-2.08, -0.99]; p-value < 0.001; I2  < 37.97%). Moreover, cinnarizine led to similar or better results when compared to active controls, including sodium valproate, topiramate, and propranolol. CONCLUSIONS: Cinnarizine can be considered a safe and effective medication for migraine prophylaxis. However, the relatively small sample size made reaching a definite conclusion impossible. Therefore, a higher number of randomized controlled trials are recommended to be taken place to clarify the situation further.

Impact of high-density EEG in presurgical evaluation for refractory epilepsy patients.

OBJECTIVE: Electrical source localization (ESI) can help to identify the seizure onset zone or propagation zone, but it is unclear how dipole localization techniques influence surgical planning. METHODS: Patients who received a high density (HD)-EEG from 7/2014-7/2019 at Stanford were included if they met the following inclusion criteria: (1) adequate epileptiform discharges were recorded for source localization analysis, (2) underwent surgical treatment, which was at least 6 months before the survey. Interictal ESI was performed with the LORETA method on age matched MRIs. Six neurophysiologists from the Stanford Epilepsy Program independently reviewed each case through an HIPPA-protected online survey. The same cases were presented again with additional data from the HD-EEG study. Ratings of how much the HD-EEG findings added value and in what way were recorded. RESULTS: Fifty out of 202 patients met the inclusion criteria, providing a total of 276 h of HDEEG recordings. All patients had video EEG recordings and at least one brain MRI, 88 % had neuropsychological testing, 78 % had either a PET or SPECT scan. Additional HD-EEG information was rated as helpful in 83.8 %, not useful in 14.4 % and misleading in 1.8 % of cases. In 20.4 % of cases the HD-EEG information altered decision-making in a major way, such as choosing a different surgical procedure, avoidance of invasive recording or suggesting placement of invasive electrodes in a lobe not previously planned. In 21.5 % of cases, HD-EEG changed the plan in a minor way, e.g., extra invasive electrodes near the previously planned sites in the same sub-lobar region. In 42.3 % cases, HD-EEG did not change their plan but provided confirmation. In cases with normal MRI, additional HD-EEG information was more likely to change physicians' decision making during presurgical process when compared to the cases with MRI-visible lesions (53.3 % vs. 34.3 %, p = 0.002). Among patients achieving Engel class I/II outcome, the concordance rate of HD-EEG and resection zone was 64.7 % versus 35.3 % with class III/IV (p = 0.028). CONCLUSION: HD-EEG assists presurgical planning for refractory epilepsy patients, with a higher yield in patients with non-lesional MRIs. Concordance of HD-EEG dipole analysis localization and resection site is a favorable outcome indicator.

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist.

Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD. In vitro experiments in cells expressing human beta adrenergic receptors demonstrate that xamoterol is highly selective for ADRB1 and functionally biased for the cAMP over the ß-arrestin pathway. Data demonstrate ADRB1-mediated attenuation of TNF-α production with xamoterol in primary rat microglia culture following LPS challenge. Finally, two independent cohorts of 5XFAD and control mice were administered xamoterol from approximately 4.0-6.5 or 7.0-9.5 months, were tested in an array of behavioral tasks, and brains were examined for evidence of neuroinflammation, and amyloid beta and tau pathology. Xamoterol reduced mRNA expression of neuroinflammatory markers (Iba1, CD74, CD14 and TGFß) and immunohistochemical evidence for microgliosis and astrogliosis. Xamoterol reduced amyloid beta and tau pathology as measured by regional immunohistochemistry. Behavioral deficits were not observed for 5XFAD mice. In conclusion, chronic administration of a selective, functionally biased, partial agonist of ADRB1 is effective in reducing neuroinflammation and amyloid beta and tau pathology in the 5XFAD model of AD.

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.

Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells. The Sig2R ligands SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), these results suggest that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPPLond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD.

ß1-adrenergic receptor activation enhances memory in Alzheimer's disease model.

OBJECTIVE: Deficits in social recognition and learning of social cues are major symptoms of neurodegenerative disorders such as Alzheimer's disease (AD). Here we studied the role of ß1-noradrenergic signaling in cognitive function to determine whether it could be used as a potential therapeutic target for AD. METHODS: Using pharmacological, biochemical and behavioral tools, we assessed social recognition and the ß1-adrenergic receptor (ADR) and its downstream PKA/phospho-CREB (pCREB) signaling cascade in the medial amygdala (MeA) in Thy1-hAPPLond/Swe+(APP) mouse model of AD. RESULTS: Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the ß1-adrenergic system. Moreover, betaxolol, a selective ß1-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of ß1-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective ß1-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB. INTERPRETATION: Our data indicate that activation of ß1-ADR in MeA is essential for learning of social cues, and that an impairment of this cascade in AD may contribute to pathogenesis and cognitive deficits. Therefore, selective activation of ß1-ADR may be used as a therapeutic approach to rescue memory deficits in AD. Further safety and translational studies will be needed to ensure the safety of this approach.

Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders.

Npas4 is a transcription factor, which is highly expressed in the brain and regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity. A deregulation of the inhibitory-excitatory balance has been associated with a variety of human developmental disorders such as schizophrenia and autism. However, not much is known about the role played by inhibitory synapses and inhibitory pathways in the development of nervous system disorders. We hypothesized that alterations in the inhibitory pathways induced by the absence of Npas4 play a major role in the expression of the symptoms observed in psychiatric disorders. To test this hypothesis we tested mice lacking the transcription factor (Npas4 knock-out mice (Npas4-KO)) in a battery of behavioral assays focusing on general activity, social behaviors, and cognitive functions. Npas4-KO mice are hyperactive in a novel environment, spend less time exploring an unfamiliar ovariectomized female, spend more time avoiding an unfamiliar male during a first encounter, show higher social dominance than their WT littermates, and display pre-pulse inhibition, working memory, long-term memory, and cognitive flexibility deficits. These behavioral deficits may replicate schizophrenia-related symptomatology such as social anxiety, hyperactivity, and cognitive and sensorimotor gating deficits. Immunohistochemistry analyses revealed that Npas4 expression is induced in the hippocampus after a social encounter and that Npas4 regulates the expression of c-Fos in the CA1 and CA3 regions of the hippocampus after a cognitive task. Our results suggest that Npas4 may play a major role in the regulation of cognitive and social functions in the brain with possible implications for developmental disorders such as schizophrenia and autism.

Sub-cellular localization, expression and functions of Sirt6 during the cell cycle in HeLa cells.

Sirtuin 6 (Sirt6), a mammalian Sir2 (silent information regulator-2) ortholog, is an NAD (+) -dependent histone deacetylase that modulates chromatin structure and genomic stability. Sirt6 knockout cells demonstrate genomic instability, and a deficiency of Sirt6 in mice leads to an aging phenotype early in life. Some nuclear sirtuins, such as Sirt7, localize to the nucleolus, and others, such as Sirt1, are mainly found in the nucleoplasm, with a minor population in the nucleolus. However, Sirt6 has been reported to be a nucleoplasmic protein that is excluded from the nucleolus. Because of the importance of a protein's localization to its interactions and functions, we evaluated Sirt6 sub-cellular localization, expression and functions throughout the cell cycle in HeLa cells. Our results showed that during interphase, Sirt6 was mostly localized to the nucleus, although it was not absent from the nucleolus. Sirt6 was enriched in the nucleolus in the G 1 phase of the cell cycle, while S phase nucleoli were almost entirely free of Sirt6. During mitosis, the Sirt6 expression level was increased, and while Sirt6 was not associated with condensed chromosomes, it partially co-localized with mitotic spindles. Cells overexpressing Sirt6 had a lower proliferation rate with a lower percentage of cells in mitosis. These findings suggest roles for Sirt6 in the nucleolus and in the mitotic phase of the cell cycle.

Vitamin D status of 6- to 7-year-old children living in Isfahan, Iran.

INTRODUCTION: Vitamin D is essential for the maintenance of good health, and vitamin D deficiency has been reported from many countries, including those with a lot of sunshine. This study was conducted to evaluate the vitamin D status in healthy 6- to 7-year-old children in Isfahan, Iran. MATERIAL AND METHODS: Five hundred and thirteen healthy children were enrolled. Serum PTH and 25-hydroxyvitamin D (25-OHD) were measured. Dietary vitamin D intake, duration of daily sunlight exposure, and percentage of exposed body surface area were determined. 25-OHD levels < 20 ng/mL and < 10 ng/mL were defined as mild and severe vitamin D deficiency, respectively. The ROC curve was utilized to obtain a local cut-off point of vitamin D deficiency. RESULTS: 25-OHD was < 20 ng/mL in 3% and < 33 ng/mL (local cut-off point of vitamin D deficiency) in 26% of subjects. Duration of sunlight exposure and daily intake of vitamin D had significant effects on serum level of vitamin D. CONCLUSIONS: A high prevalence of vitamin D deficiency in Isfahan children was observed in this study. Improvements in duration of sunlight exposure and daily intake of vitamin D can prevent vitamin D deficiency in these children.