Pharmacologic Treatment of Migraine

1998 ◽  
Vol 11 (5) ◽  
pp. 342-348
Author(s):  
John F. Rothrock
Keyword(s):  
Therapeutic Agents ◽  
Treatment Intervention ◽  
Primary Process ◽  
Pharmacologic Treatment ◽  
Trigeminovascular System ◽  
Pathologic Alteration ◽  
The Brain ◽  
Lay Public ◽  
Vexing Problem ◽  
Serotoninergic Receptors

The vascular theory of migraine proposed by Wolff, attributing migrainous symptoms to paroxysmal constriction and dilation of the cranial vasculature, held sway for over four decades and even now remains embraced by many clinicians and the lay public. Recent investigations, however, suggest that this proposed mechanism is untenable; although changes in blood vessel caliber and blood flow do occur in some patients during some attacks, they are not required for the production of migrainous symptoms and appear to be largely epiphenomena, occurring subsequent (and consequent) to another primary process. Evidence is mounting that migraine may result from a pathologic alteration of neurotransmission within the brain stem and trigeminovascular system, and one of the neurotransmitters primarily involved is serotonin. This has led to an explosion of interest in therapeutic agents which influence serotoninergic receptors, and the astounding success enjoyed by the first of these agents to be utilized clinically (sumatriptan and dihydroergotamine) and their offspring suggests that our understanding of this common and vexing problem will increase and be paralleled by the identification of yet more specific and effective treatment intervention.

scholarly journals Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Po-Chun Chu ◽  
Wen-Yen Chai ◽  
Han-Yi Hsieh ◽  
Jiun-Jie Wang ◽  
Shiaw-Pyng Wey ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Small Molecule ◽  
Focused Ultrasound ◽  
Therapeutic Agents ◽  
Tumor Treatment ◽  
Target Region ◽  
Pharmacodynamic Analysis ◽  
The Brain ◽  
Bbb Opening

Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.

scholarly journals Small-Sized Co-Polymers for Targeted Delivery of Multiple Imaging and Therapeutic Agents

Nanomaterials ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2996
Author(s):  
Julia Y. Ljubimova ◽  
Arshia Ramesh ◽  
Liron L. Israel ◽  
Eggehard Holler
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Agents ◽  
Tissue Imaging ◽  
Hydrodynamic Diameter ◽  
Blood Clearance ◽  
Deep Tissue ◽  
Flexible Polymer ◽  
Multiple Imaging ◽  
Binding Peptides ◽  
The Brain

Research has increasingly focused on the delivery of high, often excessive amounts of drugs, neglecting negative aspects of the carrier’s physical preconditions and biocompatibility. Among them, little attention has been paid to “small but beautiful” design of vehicle and multiple cargo to achieve effortless targeted delivery into deep tissue. The design of small biopolymers for deep tissue targeted delivery of multiple imaging agents and therapeutics (mini-nano carriers) emphasizes linear flexible polymer platforms with a hydrodynamic diameter of 4 nm to 10 nm, geometrically favoring dynamic juxtaposition of ligands to host receptors, and economic drug content. Platforms of biodegradable, non-toxic poly(β-l-malic acid) of this size carrying multiple chemically bound, optionally nature-derived or synthetic affinity peptides and drugs for a variety of purposes are described in this review with specific examples. The size, shape, and multiple attachments to membrane sites accelerate vascular escape and fast blood clearance, as well as the increase in medical treatment and contrasts for tissue imaging. High affinity antibodies routinely considered for targeting, such as the brain through the blood–brain barrier (BBB), are replaced by moderate affinity binding peptides (vectors), which penetrate at high influxes not achievable by antibodies.

scholarly journals Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 161
Author(s):  
Séverine André ◽  
Lionel Larbanoix ◽  
Sébastien Verteneuil ◽  
Dimitri Stanicki ◽  
Denis Nonclercq ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Therapeutic Agents ◽  
In Vivo Studies ◽  
Phage Display Technology ◽  
Brain Penetration ◽  
Wide Range ◽  
The Brain

Blood-brain barrier (BBB) crossing and brain penetration are really challenging for the delivery of therapeutic agents and imaging probes. The development of new crossing strategies is needed, and a wide range of approaches (invasive or not) have been proposed so far. The receptor-mediated transcytosis is an attractive mechanism, allowing the non-invasive penetration of the BBB. Among available targets, the low-density lipoprotein (LDL) receptor (LDLR) shows favorable characteristics mainly because of the lysosome-bypassed pathway of LDL delivery to the brain, allowing an intact discharge of the carried ligand to the brain targets. The phage display technology was employed to identify a dodecapeptide targeted to the extracellular domain of LDLR (ED-LDLR). This peptide was able to bind the ED-LDLR in the presence of natural ligands and dissociated at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide was endocytosed by endothelial cells through the caveolae-dependent pathway, proper to the LDLR route in BBB, suggesting the prevention of its lysosomal degradation. The in vivo studies performed by magnetic resonance imaging and fluorescent lifetime imaging suggested the brain penetration of this ED-LDLR-targeted peptide.

iPS models of Parkin and PINK1

2015 ◽  
Vol 43 (2) ◽  
pp. 302-307 ◽  
Author(s):  
Aleksandar Rakovic ◽  
Philip Seibler ◽  
Christine Klein
Keyword(s):  
Dopaminergic Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Therapeutic Agents ◽  
Axonal Outgrowth ◽  
Disease Mechanisms ◽  
The Central Nervous System ◽  
Degenerative Disorder ◽  
Induced Pluripotent ◽  
Druggable Targets ◽  
The Brain

Parkinson disease (PD) is a degenerative disorder of the central nervous system resulting from depletion of dopaminergic neurons and currently remains incurable despite enormous international research efforts. The development of induced pluripotent stem cell (iPSC) technology opened up the unique possibility of studying disease mechanisms in human tissue that was otherwise not accessible, such as the brain. Of particular interest are the monogenetic forms of PD as they closely resemble the more common ‘idiopathic’ PD and, through the mutated protein, provide a clear research target in iPSC-derived neurons. Recessively inherited Parkin and PTEN-induced putative kinase 1 (PINK1) mutations have been investigated in this context and the present review describes the first insights gained from studies in iPSC-derived dopaminergic neurons, which comprise abnormalities in mitochondrial and dopamine homoeostasis, microtubular stability and axonal outgrowth. These new models of PD have a high translational potential that includes the identification of druggable targets, testing of known and novel therapeutic agents in the disease-relevant tissue using well-defined read-outs and potential regenerative approaches.

scholarly journals Cerebral sterile inflammation in neurodegenerative diseases

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Kento Otani ◽  
Takashi Shichita
Keyword(s):  
Immune Responses ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Therapeutic Agents ◽  
Sterile Inflammation ◽  
Cellular Damage ◽  
Cellular Mechanisms ◽  
Abnormal Accumulation ◽  
The Brain ◽  
Lateral Sclerosis

AbstractTherapeutic strategies for regulating neuroinflammation are expected in the development of novel therapeutic agents to prevent the progression of central nervous system (CNS) pathologies. An understanding of the detailed molecular and cellular mechanisms of neuroinflammation in each CNS disease is necessary for the development of therapeutics. Since the brain is a sterile organ, neuroinflammation in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) is triggered by cerebral cellular damage or the abnormal accumulation of inflammatogenic molecules in CNS tissue through the activation of innate and acquired immunity. Inflammation and CNS pathologies worsen each other through various cellular and molecular mechanisms, such as oxidative stress or the accumulation of inflammatogenic molecules induced in the damaged CNS tissue. In this review, we summarize the recent evidence regarding sterile immune responses in neurodegenerative diseases.

scholarly journals Evaluation of Indolocarbazoles from Streptomyces sanyensis as a Novel Source of Therapeutic Agents against the Brain-Eating Amoeba Naegleria fowleri

2020 ◽  
Vol 8 (5) ◽  
pp. 789
Author(s):  
Aitor Rizo-Liendo ◽  
Ines Sifaoui ◽  
Luis Cartuche ◽  
Iñigo Arberas-Jiménez ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Ros Generation ◽  
Naegleria Fowleri ◽  
Lethal Infection ◽  
The Central Nervous System ◽  
Cell Membrane Disruption ◽  
Nægleria Fowleri ◽  
Opportunistic Pathogenic ◽  
Amoebic Meningoencephalitis ◽  
The Brain

Naegleria fowleri is an opportunistic pathogenic free-living amoeba which is able to rapidly colonize the central nervous system (CNS) and causes a lethal infection known as primary amoebic meningoencephalitis (PAM). Furthermore, more than 98% of the known cases of PAM are fatal and affect mainly children under 12 and young adults. Until now, no fully effective therapeutic agents against N. fowleri are available and hence the urgent need to find novel agents to treat PAM. At present, PAM therapy is based on the combination of amphotericin B, miltefosine, among others, with unwanted toxic effects. Recently, our team isolated various indolocarbazoles (ICZs) from the culture of a mangrove strain of Streptomyces sanyensis which showed activity against kinetoplastids and the Acanthamoeba genus. Hence, in this study, the activity of the previously isolated ICZs, staurosporine (STS), 7-oxostaurosporine (7OSTS), 4′-demethylamino-4′-oxostaurosporine, and streptocarbazole B, was evaluated against two type strains of N. fowleri. Furthermore, the performed activity assays revealed that STS was the most active ICZ presenting an inhibitory concentration 50 (IC50) of 0.08 ± 0.02 µM (SI 109.3). Moreover, STS induced programmed cell death (PCD) in the treated amoebae by triggering DNA condensation, mitochondrial disfunction, cell membrane disruption, and reactive oxygen species (ROS) generation. Therefore, STS could be a promising therapeutic agent against PAM.

scholarly journals The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2485
Author(s):  
Stephanie Sanders ◽  
Denise M. Herpai ◽  
Analiz Rodriguez ◽  
Yue Huang ◽  
Jeff Chou ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Potential Role ◽  
Therapeutic Agents ◽  
Brain Parenchyma ◽  
Low Grade ◽  
Effective Management ◽  
Diffuse Infiltration ◽  
Protein Levels ◽  
The Brain

Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor microenvironment should aid in finding more effective management of GBM. GBM-associated macrophages (GAM) comprise up to 30% of the GBM microenvironment. Therefore, exploration of GAM activity/function and their specific markers are important for developing new therapeutic agents. In this study, we identified and evaluated the expression of ALDH1A2 in the GBM microenvironment, and especially in M2 GAM, though it is also expressed in reactive astrocytes and multinucleated tumor cells. We demonstrated that M2 GAM highly express ALDH1A2 when compared to other ALDH1 family proteins. Additionally, GBM samples showed higher expression of ALDH1A2 when compared to low-grade gliomas (LGG), and this expression was increased upon tumor recurrence both at the gene and protein levels. We demonstrated that the enzymatic product of ALDH1A2, retinoic acid (RA), modulated the expression and activity of MMP-2 and MMP-9 in macrophages, but not in GBM tumor cells. Thus, the expression of ALDH1A2 may promote the progressive phenotype of GBM.

scholarly journals Affective neuroscience of the emotional BrainMind: evolutionary perspectives and implications for understanding depression

2010 ◽  
Vol 12 (4) ◽  
pp. 533-545 ◽  
Keyword(s):  
Psychiatric Disorders ◽  
Mammalian Brain ◽  
Primary Process ◽  
Affective Neuroscience ◽  
Learning Mechanisms ◽  
Negative Affects ◽  
Rough Form ◽  
Subcortical Regions ◽  
The Brain ◽  
Basic Learning

Cross-species affective neuroscience studies confirm that primary-process emotional feelings are organized within primitive subcortical regions of the brain that are anatomically, neurochemically, and functionally homologous in all mammals that have been studied. Emotional feelings (affects) are intrinsic values that inform animals how they are faring in the quest to survive. The various positive affects indicate that animals are returning to "comfort zones" that support survival, and negative affects reflect "discomfort zones" that indicate that animals are in situations that may impair survival. They are ancestral tools for living--evolutionary memories of such importance that they were coded into the genome in rough form (as primary brain processes), which are refined by basic learning mechanisms (secondary processes) as well as by higher-order cognitions/thoughts (tertiary processes). To understand why depression feels horrible, we must fathom the affective infrastructure of the mammalian brain. Advances in our understanding of the nature of primary-process emotional affects can promote the development of better preclinical models of psychiatric disorders and thereby also allow clinicians new and useful ways to understand the foundational aspects of their clients' problems. These networks are of clear importance for understanding psychiatric disorders and advancing psychiatric practice.

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