COVID-19 and neurologic manifestations: a synthesis from the child neurologist's corner.

BACKGROUND: Since December 2019, the SARS-CoV-2 virus has been a global health issue. The main clinical presentation of this virus is a flu-like disease; however, patients with diverse neurologic manifestations have also been reported. In this review, we attempt to summarize, discuss and update the knowledge of the neurologic manifestations in the pediatric population affected by SARS-CoV-2 infection and the pandemic's effects in children with neurologic diseases. DATA SOURCES: This review analyzes studies found on the PubMed database using the following keywords: Neurologic manifestations COVID-19, Neurological COVID-19, coronavirus, SARS-CoV-2, pediatric COVID-19, COVID-19 in children, MIS-C, Pediatric Inflammatory Multisystem Syndrome, Guillain Barré Syndrome, Stroke, ADEM, and Anti-NMDA encephalitis. All studies cited were published between 2004 and 2022, and represent the most relevant articles in the field. The World Health Organization COVID-19 online dashboard was assessed to obtain updated epidemiological data. RESULTS: The most common neurologic symptoms in the pediatric population are headache, seizures, encephalopathy, and muscle weakness. These can be present during COVID-19 or weeks after recovering from it. Children who presented with multi-system inflammatory syndrome had a higher incidence of neurologic manifestations, which conferred a greater risk of morbidity and mortality. Several neuro-pathophysiological mechanisms have been proposed, including direct virus invasion, hyper-inflammatory reactions, multi-systemic failure, prothrombotic states, and immune-mediated processes. On the other hand, the COVID-19 pandemic has affected patients with neurologic diseases, making it challenging to access controls, treatment, and therapies. CONCLUSIONS: Various neurologic manifestations have been associated with children's SARS-CoV-2 infection. It is important to identify and give them proper and opportune treatment because they can be potentially grave and life-threatening; some can lead to long-lasting sequelae. Different neuro-pathophysiological mechanisms have been proposed, however, a causal relationship between SARS-CoV-2 infection and neurologic manifestations remains to be proven. Patients with neurologic diseases are especially affected by COVID-19, not only by the disease itself but also by its complications and pandemic management measures.

Neurologic Features Associated With SARS-CoV-2 Infection in Children: A Case Series Report.

INTRODUCTION: Although multiple neurologic manifestations associated with SARS-CoV-2 infection have been described in adults, there is little information about those presented in children. Here, we described neurologic manifestations associated with COVID-19 in the pediatric population. METHODS: Retrospective case series report. We included patients younger than 18 years, admitted with confirmed SARS-CoV-2 infection and neurologic manifestations at our hospital in Santiago, Chile. Demographics, clinical presentations, laboratory results, radiologic and neurophysiological studies, treatment, and outcome features were described. Cases were described based on whether they presented with predominantly central or peripheral neurologic involvement. RESULTS: Thirteen of 90 (14.4%) patients admitted with confirmed infection presented with new-onset neurologic symptoms and 4 patients showed epilepsy exacerbation. Neurologic manifestations ranged from mild (headache, muscle weakness, anosmia, ageusia), to severe (status epilepticus, Guillain-Barré syndrome, encephalopathy, demyelinating events). CONCLUSIONS: We found a wide range of neurologic manifestations in children with confirmed SARS-CoV-2 infection. In general, neurologic symptoms were resolved as the systemic presentation subsided. It is essential to recognize and report the main neurologic manifestations related to this new infectious disease in the pediatric population. More evidence is needed to establish the specific causality of nervous system involvement.

S,O-Ligand-Promoted Palladium-Catalyzed C-H Functionalization Reactions of Nondirected Arenes.

Pd(II)-catalyzed C-H functionalization of nondirected arenes has been realized using an inexpensive and easily accessible type of bidentate S,O-ligand. The catalytic system shows high efficiency in the C-H olefination reaction of electron-rich and electron-poor arenes. This methodology is operationally simple, scalable, and can be used in late-stage functionalization of complex molecules. The broad applicability of this catalyst has been showcased in other transformations such as Pd(II)-catalyzed C-H acetoxylation and allylation reactions.

Mono- and Bimetallic Alkynyl Metallocenes and Half-Sandwich Complexes: A Simple and Versatile Synthetic Approach.

A general process for the synthesis of alkynyl mono and dimetallic metallocenes and half-sandwich complexes has been developed. This approach uses the addition of lithium derivatives of sandwich or half-sandwich complexes to arylsulfonylacetylenes. The reaction occurs in two steps (lithiation and anti-Michael addition to alkynylsulfone followed by elimination of the ArSO2 moiety) to form the corresponding mono- or bimetallic alkynes in clearly higher yields, simpler experimental procedures, and more environmentally benign conditions than those of the so far reported for the synthesis of this type of products. The electrochemical properties of the newly obtained complexes have also been studied.

Silver(I)-Catalyzed Addition of Phenols to Alkyne Cobalt Cluster Stabilized Carbocations.

A smooth catalytic method to use phenols as the nucleophilic partner in the Nicholas reaction has been developed. The method uses either Ag(I) or Au(I) catalysts with AgClO4 or AgBF4 as the most efficient catalysts tested. Neither additional additives nor cocatalysts were required and the formation of the corresponding phenol adducts occurred in excellent yields. The process has the single limitation of the inability of less nucleophilic phenols (4-nitrophenol) to generate the corresponding adducts. Additionally, the reaction is highly diastereoselective. DFT calculations allow a catalytic cycle to be proposed that involves trimetallic intermediates; the rate-determining step of the reaction is hydroxy-group elimination in a cobalt-silver trimetallic intermediate.

Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine.

The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 ± 0.2 µM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 ± 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Aß aggregation induced by hAChE by 30.6%.

Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia.

The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)-α-aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%.

Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles.

The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC(50) (EeAChE: 14nM); IC(50) (eqBuChE: 5.2µM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC(50) (EeAChE: 64nM); IC(50) (eqBuChE: 9.6µM] showed that this compound is a mixed-type inhibitor (K(i)=69.2nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K(+)-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.