Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABAA receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen−glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD

Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 8 (2013): e65235, doi:10.1371/journal.pone.0065235.Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.Support was provided by 2007/2008 Marine Biological Laboratory summer fellowships and NIH (NS066942A) grants to GM; Howard Hughes Medical Institute-USE Grant #52006287 to Hunter College of CUNY (LM); Muscular Dystrophy Association (MDA) and NIH (R01NS44170) grants to LJH; MDA and NIH (NS23868, NS23320, NS41170) grants to STB; NIH grant MH066179 to GB; NIH grants R01AG031311 and R01NS055951 to DMW; NIH (U01NS05225, R01NS050557, 1RC1NS068391, 1RC2NS070342) grants to RHB; R01NS067206 to DAB; ALS Association grants to GM, AT, RHB, and STB; and ALS/CVS Therapy Alliance grants to RHB, GM, AT, LJH, and DAB. RHB and AT received support from the Angel Fund. RHB also received support from the DeBourgknecht Fund for ALS Research, P2ALS and Project ALS

Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia

Background Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. Results The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. Conclusion Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia

Mixed Reality

The project called “mixed reality” started by exploring a number of technologies to do with augmented reality (AR), artificial intelligence (AI) and internet of things (IoT) in relation to contemporary art. Through speculation with technology, physical augmented reality (PAR) and its parallel to relational architecture was formally singled out and defined, AI based image analysis was used to encourage participation in the context of interactive art and a formal cloud based serverless microservice oriented software architecture along with all its artifacts and software were defined and implemented. The outcome was an interactive art installation that involved image analysis (e.g. age, gender) and emotion recognition in order to provide an effortless interaction by the interlocutors with the system through IoT based multi-colour light-emitting diodes (LEDs) and text projection

Nomethiazoles: PK/PD Study of a Novel Class of Alzheimer’s Disease Therapeutics

Since Alzheimer’s disease (AD) is a complex disease, multi-target drugs appear to be more promising in AD therapy than those targeting just one possible underlying mechanism of the disease. Therefore, a new class of hybrid molecules (Nomethiazoles) was introduced based on the role of nitric oxide in memory and neuroprotection in addition to the anti-inflammatory and neuroprotective properties of clomethiazole (CMZ). Nomethiazoles were developed through coupling of a nitrate group with the methylthiazole pharmacophore of the neuroprotectant CMZ. GT-1061, a prototype of nomethiazoles, was proved to be active in different animal models of cognition and neuroprotection, which paved the way to enter clinical trials. The major goal of this study was to evaluate the procognitive properties of two types of recently designed nomethiazoles, diaryl and triazole compounds, in step-through passive avoidance assay, a model for cognition deficit. In mice, all the novel nomethiazoles were active in reversing the cognition deficit induced by scopolamine and L-NAME (NOS inhibitor). The diaryl compounds maintained their potency longer than the triazoles. Based on the hypothesized involvement of GABA potentiation by nomethiazole, sedation was measured by accelerated rotarod performance task and compared with CMZ and GT-1061. The novel nomethiazoles were less sedative than CMZ at equimolar doses. LC-MS/MS was used to evaluate the blood brain barrier permeability of nomethiazoles. Consequently, diaryl compounds were shown to produce a higher brain plasma concentration ratio than triazole compounds. The OH metabolites formed from nomethiazoles were also detected in mice brain samples and were correlated with the sedative activity of these hybrid molecules. The study not only proved the brain bioavailability of novel nomethiazoles, but also demonstrated their procognitive action accompanied with less sedative activity when compared with CMZ and GT-106

Dermanyssus gallinae (Acari, Mesostigmata) in the Barn Swallow (Hirundo rustica) nests in Urmia suburb, North West of Iran

Ghalehjoughi, Ehsan Mohamadi, Tavassoli, Mousa, Naem, Soraya (2017): Dermanyssus gallinae (Acari, Mesostigmata) in the Barn Swallow (Hirundo rustica) nests in Urmia suburb, North West of Iran. Persian Journal of Acarology 6 (2): 95-102, DOI: 10.22073/pja.v6i2.25603, URL: https://www.mendeley.com/catalogue/7e97df90-06ca-3216-bb1c-63bd991a0e0a

Comparison of Oncologic Short Term Results of Laparoscopic Versus Open Surgery of Rectal Cancer

Background Today, with improvements in laparoscopy technique, surgery of rectal cancer is performed by laparoscopy. Objectives This study was performed to evaluate oncologic results of open versus laparoscopic surgery of rectal cancer in terms of resection margins, removal of lymph nodes and recurrence rate. Patients and Methods This descriptive-analytic study was performed on 88 patients with middle and lower rectal cancer in the two equivalent groups of laparoscopic and open surgery in Mashhad Ghaem and Omid hospitals during 2011 - 2013. Information including age, sex, number of removed and involved lymph nodes, proximal, distal, and radial margins, tumor stage and location, recurrence and disease-free survival collected in the questionnaire and analyzed using descriptive statistics and frequency distribution tables and t-test. Results Both groups of open and laparoscopic surgery had similar characteristics of age, sex, recurrence and disease-free survival, tumor margins and one-year mortality. The number of removed and involved lymph nodes was higher in the laparoscopic group (5.16 vs. 3.55, respectively, with P < 0.050, and 1.74 vs. 0.59 with P = 0.023), but the ratio of involved lymph nodes to the total number of removed lymph nodes was not different between the two groups (LNR) (P = 0.071). Tumor stage was higher in the laparoscopic group and most were in stages II and III (P < 0.001). Conclusions Laparoscopic surgery is an effective technique for safe margin and removing lymph nodes in rectal cancer

Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA_A receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen–glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD