Serotonin in the Frontal Cortex: A Potential Therapeutic Target for Neurological Disorders

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter which has broad distribution in the brain. It was discovered by Erspamer and Asero in the 1950s. 5-HT is synthesized in two steps, with Tryptophan Hydroxylase (TPH) as therate-limiting enzyme. First, tryptophan is converted to 5-hydroxytryptophan (5-HTP) by TPH. Second, the intermediate product, 5-HTP, is converted to 5-HT by aromatic acid decarboxylase (AADC). 5-HT is primarily degraded by the mitochondrial bound protein Monoamine Oxidase A (MAOA), leading to the generation of the metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Importantly, serotonin is also a substrate for melatonin synthesis. 5-HT is released from the axonal terminals of serotoninergic neurons and acts on 14 distinct receptor subtypes that are classified into 7 different families: 5-HT1 (1A, 1B, 1D, 1E, 1F), 5-HT2 (2A, 2B, and 2C), 5-HT3, 5-HT4, 5- HT5 (5A, 5B), 5-HT6, and 5-HT7. Among all these receptors, only 5-HT3 receptor is a pentameric ligand-gated ion channel composed of several subunits of which 5 different types have been identified. All other 5-HT receptors are G-protein coupled receptors which regulate the activity of the neurons expressing them. Released serotonin is transported to the presynaptic neurons by serotonin transporter (SERT or 5-HTT), a type of monoamine transporter protein.

Serotonergic neurons are located in the raphe nuclei. While the more caudal raphe nuclei project to the Peripheral Nervous System (PNS), the neurons in the dorsal and median raphe nuclei (DRN and MRN) primarily send their projections to forebrain regions. 5-HT is critically involved in the development of many cortices, such as somatosensory cortex and barrel cortex. In adult brain, 5-HT neurons project to majority of cortical areas, including the entorhinal and cingulate cortices. However, of all cortical regions, the frontal lobe contains the highest density of serotonergic terminals and 5-HT receptors. These studies indicate that 5-HT regulates cognitive and emotional functions that rely on frontal cortical activity.(Read more)

Development and Validation of Liquid Chromatography (RP-HPLC) Methodology for Estimation of Efonidipine HCl Ethanolate (EFD)

Efonidipine hydrochloride ethanolate (NZ-105), (±)-2- [Benzyl(phenyl)amino]ethyl-1,4-dihydro-2,6-dimethyl-5-(5,5-dimethy -2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitorophen-yl)-3- pyridine carboxylate hydrochloride ethanol, is a dihydropyridine calcium antagonist with aphosphonate backbone and that was discovered at Nissan Chemical Industries, Ltd. This active drug ingredient was initially studied for development as a hydrochloride salt without ethanol, obtained through the addition of hydrochloric acid to efonidipine acetone solution. It showed an excellent antihypertensive effect in patients with various kinds of hypertension (essential, severe, renal). Efonidipine has slow onset and long duration of action.

It is well known that many 1,4-dihydropyridine derivatives are subject to the first-pass effect, and that the primary metabolismstep of most derivatives involves oxidation of the dihydropyridine ring to the corresponding pyridine analogue. However, it has been suggested that efonidipine is less likely to be subject to the first-pass effect than other dihydropyridine derivatives and that its dihydropyridine ring is oxidized mainly after metabolism of the side chain. Additionally, efonidipine has distinct properties when compared with other calcium channel blockers. The studies indicated that efonidipine therapy simultaneously improves blood pressure, endothelial function, and metabolic parameters without substantially altering insulin sensitivity in non-diabetic patients with hypertension.(Read more)

The Expression of SIRT1 in Ocular Tissues.

Epigenetic alterations play important roles in a wide variety of physiological and pathological events. As one of the most important epigenetic regulators, Histone Deacetylases (HDACs) are able to deacetylate lysine residues on histone and non-histone proteins,regulating chromatin structure, gene expression and protein function. Eighteen human HDACs have been identified and grouped into 4 classes based on their homology to respective yeast orthologous. The human sirtuins family, homologs of the yeast silent information regulator 2(Sir2), belongs to class III HDACs. They are NAD+-dependent deacetylases and contain seven members (SIRT1-7) with varied functions, structures, and localizations. Among them, SIRT1 is the most extensively studied, primarily because of its regulation of diverse cellular targets and functions as well as its therapeutic potential.

Human SIRT1 comprises 747 amino acids divided into three main regions: the central core, possessing the deacetylase domain, which consists of a large NAD+-binding subdomain with a Rossmann fold and a smaller subdomain composed of a helical module and a Zn²⁺- binding module, and the N- and C-terminal domains, containing regulatory elements and binding domains for SIRT1 co-activators or repressors.(Read more) 

Magnetic Properties of Iron Oxides in the Human Globus pallidus

Iron, as the most abundant transition metal in the human brain, occurs with uneven distribution. Highest concentration of iron can be observed in areas associated with motor function (Globus pallidus, putamen, Substantia nigra) than in other areas of the human brain. Therefore, the actual role of iron accumulation in brain pathobiology isan active area of investigation nowadays.It is evident that amount of iron in brain gradually grows with age. Accumulation of iron in basal ganglia is probably associated with neuronal death leading to Alzheimer disease, Parkinson disease, epilepsy, Huntington disease, dementia with Lewy bodies, and multiple sclerosis. It was reported that iron participates in redox reactions, and catalyzes the formation of reactive oxygen species responsible for oxidative stress and damaging processes.

Iron in the human brain can be found mostly in the form of ferritin, hemosiderin (a product of ferritin breakdown) and other biomineralized oxidohydroxides and oxides such as hematite, magnetite, and maghemite. Ferritin, as an iron storage nonheme-protein with diameter up to 12 nm, consist of inorganic core (6 nm) formed of ferrihydrite and minor portion of magnetite and hematite that is enclosed by two types of polypeptides. The role of the heavy (Ft-H) form polypeptide coat of ferritin is to catalyze Fe(II) to Fe(III) ions whereas the light (Ft-L) polypeptide coat promotes the formation of ferritin iron core.The amount of Ft-H and Ft-L polypeptide coats changes during ageing and the magnetic properties of ferritin can also alter.(Read More)

Adjunctive Treatment Considerations for the Addressment of Inflammation in Neuromuscular Disorders.

At the root of many of society’s major health concerns plaguing millions of Americans each year is the concept of inflammation. Encompassing cardiovascular, oncologic, dermatologic, painmanagement, and neurologic diseases, the peripheral and systemic manifestations of inflammation has been increasingly shown to be a major culprit in disease spread. Broad examples of this can be seen in various neurologic disease states.

Demyelinating diseases such as Multiple Sclerosis and degenerative changes associated with dementia have many factors with inflammation being one of those. The inflammatory cascade with its incorporation of pro inflammatory cytokines and transcriptional factors has been shown to be suggestive in the pathophysiology of these diseases. Similarly, glial cells, acting as neural supports, have been shown to play a role in the production of these same pro inflammatory cells (IL-1B, IL-6, IL-8, TNF-alpha). The overproduction of these mediators is suggestive of neurodegenerative progression in both acute (ischemic injury) and chronic degenerative neural disorders. Acknowledgement and addressment of the inflammatory cascade has led to novel treatment strategies such as the use of sirtuins.(Read more)

Essential Oil Chemotypes of Three Ocimum Species Found in Sierra Leone and Nigeria.

The family Lamiaceae of which the genus Ocimum belongs is composed of diverse and rich source of essential oil containing plants. Ocimum contains between fifty to one hundredand fifty species of herbs and shrubs from the tropical regions of Asia, Africa, and Central and South America. O. gratissimum L. is referred to as holy basil. In Sierra Leone, it is known as “Tea bush” (Krio) and “orgbethor” (Themne) while it is known as “efirin nla” in the Yoruba speaking culture of Nigeria. O. basilicum L. is also referred to as sweet basil. It is known as “Patmenji” (Krio) and “Sorow” (Themne) of Sierra Leone and “efinrin wewe” by the Yorubas. O. americanum L. (synonym of O. canum Sims) is known as American basil or hoary basil. 

In Sierra Leone both the available varieties of O. americanum L and O. basilicum L. are used in culinary as “Patmengy” indiscriminately. The different varieties of O. gratissimum L. [implying different chemotypes] have been used extensively in the traditional system of medicine in many countries as had been reviewed. The main issues of concern with the use of herbal drugs remain safety, validation of claims and standardisation of product. There exist the problems of significant variation in the content of Ocimum plants across and within species, with implication of varied biological activities.(Read more)

Berberine Protects against Hydrogen Peroxide-Induced Oxidative Damage in PC12 Cells through Activation of ERK1/2 Pathway.

Neurodegenerative diseases (ND), such as Alzheimer's (AD) and Parkinson's disease (PD), are chronic degenerative pathologies of the Central Nervous System (CNS). NDs arecharacterized by progressive loss of specific neurons which further leads to adecline in brain functions. Despite the fact that pathologies have different clinical features, there are some common hallmarks, such as synaptic dysfunctioning, oxidative stress, and inflammation. The NDs are caused by an enhancement of ROS production via mitochondria and NADPH oxidase (NOX), which seems to account for tissue injury and neurodegeneration. 

Nowadays, NDs are chronic and incurable conditions, and the disabling effects may continue for years or even decades representing an enormous disease load, regarding human suffering and economic cost. In neuronal cells, the over production of ROS is considered as one of the risk factors for NDs. Disruption of redox homeostasis is a key phenotype of many pathological conditions. Hydrogen peroxide (H₂O₂), the main source of ROS, can cause cell membrane injury as well as lipid peroxidation and DNA damage in variety cells. However, antioxidants were able to protect cells against H₂O₂-induced cell death via reducing ROS production.(Read more)