Antiepileptic Drugs as Potential Dementia Prophylactics Following Traumatic Brain Injury.

Seizures and other forms of neurovolatility are emerging as druggable prodromal mechanisms that link traumatic brain injury (TBI) to the progression of later dementias. TBI neurotrauma has both acute and long-term impacts on health, and TBI is a leading risk factor for dementias, including chronic traumatic encephalopathy and Alzheimer's disease. Treatment of TBI already considers acute management of posttraumatic seizures and epilepsy, and impressive efforts have optimized regimens of antiepileptic drugs (AEDs) toward that goal. Here we consider that expanding these management strategies could determine which AED regimens best prevent dementia progression in TBI patients. Challenges with this prophylactic strategy include the potential consequences of prolonged AED treatment and that a large subset of patients are refractory to available AEDs. Addressing these challenges is warranted because the management of seizure activity following TBI offers a rare opportunity to prevent the onset or progression of devastating dementias.

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders.

Neurodegenerative disorders, such as Alzheimer's disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A-N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3ß, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3ß (ΔG: -8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M-1), NMDA (ΔG: -9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M-1), and BACE-1 (ΔG: -9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M-1). It showed a 25-fold higher affinity with GSK-3ß, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3ß-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.

Antibacterial efficacy of synthesized silver nanoparticles of Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O) against biofilm forming meningitis causing microbes.

Actinobacteria obtained from the least explored Indian regions were studied for their ability to suppress meningitis-causing bacteria in nanoparticle form. Drug-resistant bacteria and long-term treatment with different medications make meningitis control complicated. Thus, new meningitis drugs are required to combat MDR bacteria. In this study, secondary metabolites isolated from actinomycetes strains, Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O), were employed to synthesize silver nanoparticles (AgNPs) at 37 °C for seven days incubation. UV-Vis spectroscopy, TEM, FTIR, and HPLC studies were used for the confirmation of the synthesis of AgNPs. Furthermore, these NPs demonstrated antibacterial and antibiofilm activities against meningitis-causing bacteria. The average size of LA2(R) and LA2(O) isolated secondary metabolites mediated AgNPs was observed to be 27 ± 1and 29 ± 2 nm by TEM analysis. FTIR study of RAgNPs and OAgNPs revealed that presence of peaks with positions of 1637.17 cm1 and 1636.10 cm1 for C=O amide group appearances in the amide I linkage. These NPs were effective against bacterial pathogens such as S. pneumoniae, H. influenzae, and N. meningitidis and confirmed by their MICs, i.e., 109.4, 120.60, and 138.80 µg/ml of RAgNPs and 105.80, 114.40 and 129.06 µg/ml of OAgNPs, respectively. Additionally, the production of biofilms is impeded by these nanoparticles on S. pneumoniae, H. influenzae, and N. meningitidis by 73.14%, 71.89% and 64.81%, respectively. These findings confirm the potential role of synthesized AgNPs against biofilm forming meningitis causing Multidrug resistance (MDR) microbes.

Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects.

Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs' role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.

Seizures are a druggable mechanistic link between TBI and subsequent tauopathy.

Traumatic brain injury (TBI) is a prominent risk factor for dementias including tauopathies like chronic traumatic encephalopathy (CTE). The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we test the putative role of seizures in promoting the spread of tauopathy. We introduce 'tauopathy reporter' zebrafish expressing a genetically encoded fluorescent Tau biosensor that reliably reports accumulation of human Tau species when seeded via intraventricular brain injections. Subjecting zebrafish larvae to a novel TBI paradigm produced various TBI features including cell death, post-traumatic seizures, and Tau inclusions. Bath application of dynamin inhibitors or anticonvulsant drugs rescued TBI-induced tauopathy and cell death. These data suggest a role for seizure activity in the prion-like seeding and spreading of tauopathy following TBI. Further work is warranted regarding anti-convulsants that dampen post-traumatic seizures as a route to moderating subsequent tauopathy.

Traumatic brain injury can result from direct head concussions, rapid head movements, or a blast wave generated by an explosion. Traumatic brain injury often causes seizures in the short term and is a risk factor for certain dementias, including Alzheimer's disease and chronic traumatic encephalopathy in the long term. A protein called Tau undergoes a series of chemical changes in these dementias that makes it accumulate, form toxic filaments and kill neurons. The toxic abnormal Tau proteins are initially found only in certain regions of the brain, but they spread as the disease progresses. Previous studies in Alzheimer's disease and other diseases where Tau proteins are abnormal suggest that Tau can spread between neighboring neurons and this can be promoted by neuron activity. However, scientists do not know whether similar mechanisms are at work following traumatic brain injury. Given that seizures are very common following traumatic brain injury, could they be partly responsible for promoting dementia? To investigate this, researchers need animal models in which they can measure neural activity associated with traumatic brain injury and observe the spread of abnormal Tau proteins. Alyenbaawi et al. engineered zebrafish so that their Tau proteins would be fluorescent, making it possible to track the accumulation of aggregated Tau protein in the brain. Next, they invented a simple way to perform traumatic brain injury on zebrafish larvae by using a syringe to produce a pressure wave. After this procedure, many of the fish exhibited features consistent with progression towards dementia, and seizure-like behaviors. The results showed that post-traumatic seizures are linked to the spread of aggregates of abnormal Tau following traumatic brain injury. Alyenbaawi et al. also found that anticonvulsant drugs can lower the levels of abnormal Tau proteins in neurons, preventing cell death, and could potentially ameliorate dementias associated with traumatic brain injury. These drugs are already being used to prevent post-traumatic epilepsy, but more research is needed to confirm whether they reduce the risk or severity of Tau-related neurodegeneration.

Prion-Like Propagation Mechanisms in Tauopathies and Traumatic Brain Injury: Challenges and Prospects.

The accumulation of tau protein in the form of filamentous aggregates is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). These dementias share traumatic brain injury (TBI) as a prominent risk factor. Tau aggregates can transfer between cells and tissues in a "prion-like" manner, where they initiate the templated misfolding of normal tau molecules. This enables the spread of tau pathology to distinct parts of the brain. The evidence that tauopathies spread via prion-like mechanisms is considerable, but work detailing the mechanisms of spread has mostly used in vitro platforms that cannot fully reveal the tissue-level vectors or etiology of progression. We review these issues and then briefly use TBI and CTE as a case study to illustrate aspects of tauopathy that warrant further attention in vivo. These include seizures and sleep/wake disturbances, emphasizing the urgent need for improved animal models. Dissecting these mechanisms of tauopathy progression continues to provide fresh inspiration for the design of diagnostic and therapeutic approaches.