Discovery of gallic acid-based mitochondriotropic antioxidant attenuates LPS-induced neuroinflammation.

Mitochondria are complex organelle that plays a pivotal role in energy metabolism, regulation of stress responses, and also serve as a major hub for biosynthetic processes. In addition to their well-established function in cellular energetics, it also serves as the primary site for the origin of intracellular reactive oxygen species (ROS), which function as signaling molecules and can lead to oxidative stress when generated in excess. Moreover, mitochondrial dysfunction is one of the leading cause of neuroinflammation.

Generation of Functional Neurons from Mesenchymal Stem Cells Using Neural Differentiator and Engineered Peptide Hydrogel: Potential Therapeutic Lead for Traumatic Brain Injury.

Traumatic brain injuries (TBIs) cause multifaceted disruption in the neural network, initiate huge inflammation processes, and form glial scars that result in severe damage to the brain. Thus, the treatment of TBI is a challenging task. To address this challenge, a newer and innovative approach is extremely important to develop a successful therapeutic strategy.

Logic "AND Gate Circuit" Based Mussel Inspired Polydopamine Nanocomposite as Bioactive Antioxidant for Management of Oxidative Stress and Neurogenesis in Traumatic Brain Injury.

In the intricate landscape of Traumatic Brain Injury (TBI), the management of TBI remains a challenging task due to the extremely complex pathophysiological conditions and excessive release of reactive oxygen species (ROS) at the injury site and the limited regenerative capacities of the central nervous system (CNS). Existing pharmaceutical interventions are limited in their ability to efficiently cross the blood-brain barrier (BBB) and expeditiously target areas of brain inflammation. In response to these challenges herein, we designed novel mussel inspired polydopamine (PDA)-coated mesoporous silica nanoparticles (PDA-AMSNs) with excellent antioxidative ability to deliver a new potential therapeutic GSK-3β inhibitor lead small molecule abbreviated as Neuro Chemical Modulator (NCM) at the TBI site using a neuroprotective peptide hydrogel (PANAP).

Hydrophobic C-Terminal Peptide Analog Aβ Protects the Neurons from Aβ-Induced Toxicity.

Spontaneous aggregation of amyloid beta (Aβ) leads to the formation of neurotoxic senile plaque considered as the most crucial event in Alzheimer's disease (AD) progression. Inhibition or disruption of this deadly aggregate formation is one of the most efficient strategies for the development of potential therapeutics, and extensive research is in progress by various research groups. In this direction, the development of a peptide analogous to that of the native Aβ peptide is an attractive strategy.

Molecular mechanism of cognitive impairment associated with Parkinson's disease: A stroke perspective.

Parkinson's disease (PD) is a common neurological illness that causes several motor and non-motor symptoms, most characteristically limb tremors and bradykinesia. PD is a slowly worsening disease that arises due to progressive neurodegeneration of specific areas of the brain, especially the substantia nigra of the midbrain. Even though PD has continuously been linked to a higher mortality risk in numerous epidemiologic studies, there have been significant discoveries regarding the connection between PD and stroke.

Controlling Amyloid Beta Peptide Aggregation and Toxicity by Protease-Stable Ligands.

Polymerization of soluble amyloid beta (Aβ) peptide into protease-stable insoluble fibrillary aggregates is a critical step in the pathogenesis of Alzheimer's disease (AD). The N-terminal (NT) hydrophobic central domain fragment 16KLVFF20 plays an important role in the formation and stabilization of β-sheets by self-recognition of the parent Aβ peptide, followed by aggregation of Aβ in the AD brain. Here, we analyze the effect of the NT region inducing β-sheet formation in the Aβ peptide by a single amino acid mutation in the native Aβ peptide fragment.

High-Affinity Fluorescent Probes for the Detection of Soluble and Insoluble Aβ Deposits in Alzheimer's Disease.

The overproduction and deposition of the amyloid-β (Aβ) aggregates are accountable for the genesis and development of the neurologic disorder Alzheimer's disease (AD). Effective medications and detection agents for AD are still deficient. General challenges for the diagnosis of Aβ aggregates in the AD brain are (i) crossing the blood-brain barrier (BBB) and (ii) selectivity to Aβ species with (iii) emission maxima in the 500-750 nm region.

Vanillin Benzothiazole Derivative Reduces Cellular Reactive Oxygen Species and Detects Amyloid Fibrillar Aggregates in Alzheimer's Disease Brain.

The misfolding of amyloid beta (Aβ) peptides into Aβ fibrillary aggregates is a major hallmark of Alzheimer's disease (AD), which responsible for the excess production of hydrogen peroxide (HO), a prominent reactive oxygen species (ROS) from the molecular oxygen (O) by the reduction of the Aβ-Cu(I) complex. The excessive production of HO causes oxidative stress and inflammation in the AD brain. Here, we have designed and developed a dual functionalized molecule VBD by using π-conjugation (C═C) in the backbone structure.

Short Peptoid Evolved from the Key Hydrophobic Stretch of Amyloid-β42 Peptide Serves as a Potent Therapeutic Lead of Alzheimer's Disease.

Amyloid-β 42(Aβ42), an enzymatically cleaved (1-42 amino acid long) toxic peptide remnant, has long been reported to play the key role in Alzheimer's disease (AD). Aβ42 also plays the key role in the onset of other AD-related factors including hyperphosphorylation of tau protein that forms intracellular neurofibrillary tangles, imbalances in the function of the neurotransmitter acetylcholine, and even generation of reactive oxygen species (ROS), disrupting the cytoskeleton and homeostasis of the cell. To address these issues, researchers have tried to construct several strategies to target multiple aspects of the disease but failed to produce any clinically successful therapeutic molecules.

Design and Development of Benzothiazole-Based Fluorescent Probes for Selective Detection of Aβ Aggregates in Alzheimer's Disease.

The formation and accumulation of amyloid beta (Aβ) peptide are considered the crucial events that are responsible for the progression of Alzheimer's disease (AD). Herein, we have designed and synthesized a series of fluorescent probes by using electron acceptor-donor end groups interacting with a π-conjugating system for the detection of Aβ aggregates. The chemical structure of these probes denoted as RMs, having a conjugated π-system (C═C), showed a maximum emission in PBS (>600 nm), which is the best range for a fluorescent imaging probe.

Extracellular Matrix (ECM)-Mimicking Neuroprotective Injectable Sulfo-Functionalized Peptide Hydrogel for Repairing Brain Injury.

Brain injury can lead to the loss of neuronal functions and connections, along with the damage of the extracellular matrix (ECM). Thus, it ultimately results in devastating long-term damage, and recovery from this damage is a challenging task. To address this issue, we have designed a sulfo-group-functionalized injectable biocompatible peptide hydrogel, which not only mimics the ECM and supports the damaged neurons but also releases a neurotrophic factor around the injured sites of the brain in the presence of the matrix metalloproteinase 9 (MMP9) enzyme.

Rhodamine-Based Metal Chelator: A Potent Inhibitor of Metal-Catalyzed Amyloid Toxicity.

Alzheimer's disease (AD) exhibits a multitude of syndromes which add up to its complex nature. In AD, amyloid plaques are deposited along with abnormal accumulation of transition-metal ions. These transition-metal ions are redox-active and help to induce the formation of various polymorphic forms of amyloid-β.

Human Serum Albumin-Inspired Glycopeptide-Based Multifunctional Inhibitor of Amyloid-β Toxicity.

In Alzheimer's disease (AD), insoluble Aβ42 peptide fragments self-aggregate and form oligomers and fibrils in the brain, causing neurotoxicity. Further, the presence of redox-active metal ions such as Cu enhances the aggregation process through chelation with these Aβ42 aggregates as well as generation of Aβ42-mediated reactive oxygen species (ROS). Herein, we have adopted a bioinspired strategy to design and develop a multifunctional glycopeptide hybrid molecule (Glupep), which can serve as a potential AD therapeutic.

Generation of Neurospheres from Mixed Primary Hippocampal and Cortical Neurons Isolated from E14-E16 Sprague Dawley Rat Embryo.

Primary neuron culture is an essential technique in the field of neuroscience. To gain deeper mechanistic insights into the brain, it is essential to have a robust in vitro model that can be exploited for various neurobiology studies. Though primary neuron cultures (i.

In Silico Approach for Designing Potent Neuroprotective Hexapeptide.

Alzheimer's disease (AD) is a constantly recurring neurodegenerative disease that deteriorates over a period of time. In this pathology, connections between neurons become extremely damaged due to the deposition of senile plaques in the membrane region, which results in abnormal signal transduction processes. Also, the intracellular microtubule networks are disrupted in the hyperphosphorylated tau cascade of AD.

Dual-Arm Nanocapsule Targets Neuropilin-1 Receptor and Microtubule: A Potential Nanomedicine Platform.

A multiarm nanomedicine template has been designed following bottom-up approach, which target neuropilin-1 (Nrp-1) receptor of cancer cells. Through this venture, we discovered that cucurbit [6] uril (CB [6]) binds with tubulin close to binding pocket of vinblastine site and perturbs tubulin polymerization. To increase the specificity of gold nanoparticle (GNP) toward Nrp-1-rich cancer cells, we further modified this GNP with Nrp-1 receptor-specific short peptide (CGNKRTR).

Potential Neuroprotective Peptide Emerged from Dual Neurotherapeutic Targets: A Fusion Approach for the Development of Anti-Alzheimer's Lead.

Amyloid-beta (Aβ) peptide misfolds into fibrillary aggregates (β-sheet) and is deposited as amyloid plaques in the cellular environment, which severely damages intraneuronal connections leading to Alzheimer's disease (AD) pathogenesis. Furthermore, neurons are rich in tubulin/microtubules, and the intracellular network of microtubules also gets disrupted by the accumulation of Aβ fiber in the brain. Hence, development of new potent molecules, which can simultaneously inhibit Aβ fibrillations and stabilize microtubules, is particularly needed for the efficient therapeutic application in AD.

Power of Tyrosine Assembly in Microtubule Stabilization and Neuroprotection Fueled by Phenol Appendages.

Microtubules play a crucial role in maintenance of structure, function, axonal extensions, cargo transport, and polarity of neurons. During neurodegenerative diseases, microtubule structure and function get severely damaged due to destabilization of its major structural proteins. Therefore, design and development of molecules that stabilize these microtubule networks have always been an important strategy for development of potential neurotherapeutic candidates.

Neuro-Regenerative Choline-Functionalized Injectable Graphene Oxide Hydrogel Repairs Focal Brain Injury.

Brain damage is associated with spatial imbalance of cholinergic system, which makes severe impact in recovery of damaged neurons of brain. Therefore, maintenance of cholinergic system is extremely important. Here, we fabricated an injectable hydrogel with acetylcholine-functionalized graphene oxide and poly(acrylic acid).

Discovery of Neuroregenerative Peptoid from Amphibian Neuropeptide That Inhibits Amyloid-β Toxicity and Crosses Blood-Brain Barrier.

Development of potential therapeutics for Alzheimer's disease (AD) requires a multifaceted strategy considering the high levels of complexity of the human brain and its mode of function. Here, we adopted an advanced strategy targeting two key pathological hallmarks of AD: senile plaques and neurofibrillary tangles. We derived a lead short tetrapeptide, Ser-Leu-Lys-Pro (SLKP), from a dodeca-neuropeptide of amphibian (frog) brain.

Neurosphere Development from Hippocampal and Cortical Embryonic Mixed Primary Neuron Culture: A Potential Platform for Screening Neurochemical Modulator.

Reconstitution of a complex biological structure or system following a simple and facile strategy using minimum physiochemical cues is challenging for an in-depth understanding of the system. In particular, the brain is a highly sophisticated and complex network of trillions of neurons and glial cells that controls function of our body. Understanding this complex machinery requires an innovative and simple bottom-up approach.

Genesis of Neuroprotective Peptoid from Aβ30-34 Inhibits Aβ Aggregation and AChE Activity.

Aβ peptide and hyper-phosphorylated microtubule associated protein (Tau) aggregation causes severe damage to both the neuron membrane and key signal processing microfilament (microtubule) in Alzheimer's disease (AD) brains. To date, the key challenge is to develop nontoxic, proteolytically stable amyloid inhibitors, which can simultaneously target multiple pathways involved in AD. Various attempts have been made in this direction; however, clinical outcomes of those attempts have been reported to be poor.

Peptide-Based Acetylcholinesterase Inhibitor Crosses the Blood-Brain Barrier and Promotes Neuroprotection.

Design and development of acetylcholinesterase (AChE) inhibitor has tremendous implications in the treatment of Alzheimer's disease (AD). Here, we have adopted a computational approach for the design of a peptide based AChE inhibitor from its active site. We identified an octapeptide, which interacts with the catalytic anionic site (CAS) of AChE enzyme and inhibits its activity.