A Mini Review on the Various Facets Effecting Brain Delivery of Magnesium and Its Role in Neurological Disorders.

Magnesium is an essential cation present in the body that participates in the regulation of various vital body functions. Maintaining normal level of magnesium is essential for proper brain functions by regulating the activities of numerous neurotransmitters and their receptors. Various studies have been reported that magnesium level is found to be declined in both neurological and psychiatric diseases. Declined magnesium level in the brain initiates various cumbersome effects like excitotoxicity, altered blood-brain permeability, oxidative stress, and inflammation, which may further worsen the disease condition. Shreds of evidence from the experimental and clinical studies proved that exogenous administration of magnesium is useful for correcting disease-induced alterations in the brain. But one of the major limiting factors in the use of magnesium for treatment purposes is its poor blood-brain barrier permeability. Various approaches like the administration of its organic salts as pidolate and threonate forms, and the combination with polyethylene glycol or mannitol have been tried to improve its permeability to make magnesium as a suitable drug for different neurological disorders. These results have shown their experimental efficacy in diseased animal models, but studies regarding the safety and efficacy in human subjects are currently underway. We present a comprehensive review on the role of magnesium in the maintenance of normal functioning of the brain and various approaches for improving its BBB permeability.

Formulation and evaluation of magnesium sulphate nanoparticles for improved CNS penetrability.

Magnesium (Mg2+) is the fourth most abundant cation in the human body and is involved in maintaining varieties of cellular and neurological functions. Magnesium deficiency has been associated with numerous diseases, particularly neurological disorders, and its supplementation has proven beneficial. However, magnesium therapy in neurological diseases is limited because of the inability of magnesium to cross the blood-brain barrier (BBB). The present study focuses on developing magnesium sulphate nanoparticles (MGSN) to improve blood-brain barrier permeability. MGSN was prepared by precipitation technique with probe sonication. The developed formulation was characterized by DLS, EDAX, FT-IR and quantitative and qualitative estimation of magnesium. According to the DLS report, the average size of the prepared MGSN is found to be 247 nm. The haemocompatibility assay studies revealed that the prepared MGSN are biocompatible at different concentrations. The in vitro BBB permeability assay conducted by Parallel Artificial Membrane Permeability Assay (PAMPA) using rat brain tissue revealed that the prepared MGSN exhibited enhanced BBB permeability as compared to the marketed i.v. MgSO4 injection. The reversal effect of MGSN to digoxin-induced Na+/K+ ATPase enzyme inhibition using brain microslices confirmed that MGSN could attenuate the altered levels of Na+ and K+ and is useful in treating neurological diseases with altered expression of Na+/K+ ATPase activity.

Cortical spreading depression: culprits and mechanisms.

Cortical spreading depression or CSD is an electrophysiological phenomenon affecting various perspectives of brain physiology such as ionic balance, neurotransmitter level, and blood flow in the brain. This phenomenon has greater impact on the brain function and results in the pathological contribution of many diseases in humans such as migraine with aura, stroke, and traumatic brain injury. Various factors such as nutrition, stress, sleep, age, alcohol, inflammation and oxidative stress worsen the condition and affect CSD susceptibility. The underlying mechanisms such as ionic imbalance and neurotransmitters' alteration are interconnected and may worsen the condition of CSD. Thus, correction of these main culprits might ameliorate the cumbersome effect of CSD, thereby providing benefits in diseases associated with CSD. This review collates most of the triggering factors that makes one prone to the CSD condition along with its underlying mechanisms.

Non alcoholic palm nectar from Cocos nucifera as a promising nutraceutical preparation.

Nonalcoholic Palm Nectar from Cocos nucifera (NPNC), a bio-refresher obtained from the juvenile inflorescence of coconut palm; is prominent as a nutritional health drink. The aim of this study was to investigate the nutritional and medicinal properties of NPNC and its products; sugar (NPNCS) and honey (NPNCH). The collected samples were subjected to physicochemical evaluations such as pH, Titrable Acidity, Total Soluble Solids, and Ash value, using standard techniques. The analysis revealed the suitability of NPNC as a natural health drink over conventionally available beverage. The elemental compositions of the samples were determined by using Inductive Coupled Plasma-Atomic Emission Spectrometry and demonstrated that NPNCH is enriched with iron and NPNCS with calcium. Vitamin C present in the samples was determined by using 2,6-Dichlorophenol indophenol redox titration method. Hydrolysable polyphenols, tannins, and flavonoids are determined by Folin-Ciocalteu, by Folin-Denis's technique and by aluminium chloride colorimetric methods, respectively. In NPNC, the dominance of Vitamin C as antioxidant is observed. Diuretic activity of samples was determined by Lipschitz method, and the results revealed that NPNC exhibited significant diuretic activity, comparable with furosemide. Immunomodulatory activities of the samples were evaluated by using indirect hemagglutination test and by using delayed type hypersensitivity (DTH) response. NPNC, NPNCS, and NPNCH exhibited stimulatory effect on humoral and cell-mediated immunity, which is comparable with that of standard immunomodulator levamizole. Subacute toxicity studies of selected samples were done in Wistar rats and the results proved the boicompatibility of the samples without systemic toxic effects. PRACTICAL APPLICATIONS: The use of commercially available carbonated beverages and energy drinks in young adults are associated with negative health outcomes with increased incidence of diabetes, sleep disturbances, and dental problems. Even though, such complications are there, the energy drink industries have grown dramatically accounting for major percentage of market sale. Researchers are in search for natural health drinks with some medicinal value to avoid the negative impact on consumers' health. Nonalcoholic Palm Nectar from Cocos nucifera (NPNC) is considered as zero alcoholic natural health drink. The focus of this study is to reveal the potential medicinal properties of NPNC and its products; honey (NPNCH) and sugar (NPNCS). If the nutritional and medicinal values of the selected preparations from natural sources can be proved with scientific evidence, its ability to beat commercially available carbonated beverages and energy drinks with negative health consequences may get widespread acceptance.

A Review on Newer Ocular Drug Delivery Systems with an Emphasis on Glaucoma.

Glaucoma is an irreversible condition resulting from the increase in intraocular pressure (IOP); which leads to permanent loss of vision with the destruction of retinal ganglion cells (RGCs). The IOP elevations are controlled in normal by the physiological flow of aqueous humour. A population with age above 40 is more susceptible to glaucoma. Other factors like gender, genetics, race etc. plays major roles in the development of the disease. Current treatment methods available for the disease includes drugs come under the classes of beta receptor blockers, carbonic anhydrase inhibitors, cholinergic agonists, prostaglandins etc. N-methyl-D-aspartate (NMDA) antagonists, inducible nitric oxide synthase (iNOS) inhibition, cytoskeletal agents, Rho-kinase inhibitors etc are few novel targets sites which are in research focus for the treatment of the disease. Developments in nanomedicine are also being evaluated for their potential in treating the growing glaucomatous population. Nanosystems are suggested to avoid the difficulties in tackling the various ocular barriers to a limit, help to decrease the instillation frequency of topical medication and can provide drug delivery in a sustained or controlled manner. This review focuses on the current and emerging treatment methods for glaucoma along with some of the nanoformulations for ocular drug delivery.

'Magnesium'-the master cation-as a drug-possibilities and evidences.

Magnesium (Mg2+) is the 2nd most abundant intracellular cation, which participates in various enzymatic reactions; there by regulating vital biological functions. Magnesium (Mg2+) can regulate several cations, including sodium, potassium, and calcium; it consequently maintains physiological functions like impulse conduction, blood pressure, heart rhythm, and muscle contraction. But, it doesn't get much attention in account with its functions, making it a "Forgotten cation". Like other cations, maintenance of the normal physiological level of Mg2+ is important. Its deficiency is associated with various diseases, which point out to the importance of Mg2+ as a drug. The roles of Mg2+ such as natural calcium antagonist, glutamate NMDA receptor blocker, vasodilator, antioxidant and anti-inflammatory agent are responsible for its therapeutic benefits. Various salts of Mg2+ are currently in clinical use, but their application is limited. This review collates all the possible mechanisms behind the behavior of magnesium as a drug at different disease conditions with clinical shreds of evidence.

Ethosomal Gel Formulation of Alpha Phellandrene for the Transdermal Delivery in Gout.

Purpose: Purpose was to improve the skin compatibility and permeability of alpha phellandrene through an ethosomal gel formulation for the treatment of gout; as the oral use of the drug is reported to cause gastrointestinal disturbances and toxicities. Methods: Alpha phellandrene loaded ethosomal formulation (APES) was prepared by cold method for the treatment of gout. APES were loaded into carbopol gel (APEG) by dispersion method. Physico-chemical characterizations of the APES were done by dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR) etc. In vitro release, permeation, haemo-compatibility and anti-inflammatory studies were conducted. Results: APES showed a particle size of 364.83 ± 45.84 nm. The entrapment efficiency of the optimized formulation is found as 95.06 ± 2.51%. Hemolysis data indicated that APES does not cause any significant hemolysis. In vitro drug release studies were carried out using dialysis membrane technique and the amount of drug released from APES & APEG is found to be 95% and 94.21% respectively after 5 and6 hours. Kinetic data analysis revealed that APES & APEG follows first order and zero order release kinetics, respectively. The anti-inflammatory activity studies of the formulation are done by estimating its inhibitory effects on cyclooxygenase II (COX) II, lipoxygenase-5 (LOX-5), Myeloperoxidase (MPO), Inducible nitric oxide synthase (INOS) & cellular nitrite level using RAW 264.7 cells. The significant inhibition in the activities of the enzymes implies the anti-inflammatory activity of the formulations. Skin permeation study was carried out using porcine skin and revealed that the permeation of alpha phellandrene is increased from APES & APEG when compared with alpha-phellandrene solution (APS). Skin deposition study of APS, APES & APEG revealed better drug deposition from APEG (48.799 ± 1.547µg/cm2 ) after 24 hours when compared with APS & APES. Conclusion: Overall results indicate that the ethosomal formulation of alpha phellandrene through transdermal route is an effective alternative for oral use of the drug.

In vivo anti-psoriatic activity, biodistribution, sub-acute and sub-chronic toxicity studies of orally administered methotrexate loaded chitin nanogel in comparison with methotrexate tablet.

The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5.143 mg/kg dose, followed by MTX tablet and are lowest in MCNG at 2.715 mg/kg dose. MCNG at the highest dose of 5.143 mg/kg caused liver, lung and kidney toxicities on sub acute toxicity studies and MTX tablet was found to be toxic on liver and lung on sub chronic toxicity studies. MCNG 2.715 mg/kg was found to be safe on both sub acute and sub chronic administrations, suggesting that it can provide sufficient serum and tissue level of methotrexate necessary to clear psoriatic lesions, without inducing systemic toxicity and expected to be a better alternative for orally administered conventional methotrexate tablet for patients who need systemic medications for psoriasis.

Anti-psoriatic and toxicity evaluation of methotrexate loaded chitin nanogel in imiquimod induced mice model.

Methotrexate loaded chitin nanogel (MCNG) was formulated for its topical use in psoriasis. MCNG was characterized by DLS, TEM and FTIR. The MCNG particles were spherical in shape with size of 196±14nm, having surface charge of +9.21±0.42 mv. MCNG exhibited greater swelling and drug release at acidic pH than neutral and alkaline conditions. The treatment with MCNG showed significant level of toxicity on HaCaT and THP-1 cells and was taken up well by HaCaT cells as revealed by fluorescent microscopy. MCNGs exhibited significant anti-inflammatory activity as revealed by the inhibitory effects observed on the activity of COX-2 and LOX-5 enzymes expressed in THP-1 cells. Skin permeation studies revealed an increased trasdermal flux of methotrexate from MCNG with loosened stratum corneum and other epidermal layers of skin in comparison with control methotrexate solution treated samples. Significant anti-psoriatic efficacy on imiquimod (IMQ) induced model of psoriasis without any dermal and systemic toxicities suggest that it as an ideal delivery platform for topical delivery of methotrexate in psoriasis. Thus it is expected to become a better alternative for the oral delivery of methotrexate in the selected disease.

Comparative anti-psoriatic efficacy studies of clobetasol loaded chitin nanogel and marketed cream.

In the present study chitin nanogel loaded with anti-psoriatic drug clobetasol was developed (CLCNG) for its topical delivery in psoriasis. CLCNG had the particle size of 132±14nm, with gel like consistency, stability in refrigerator, having higher drug release properties at acidic pH. CLCNG exhibited significant toxicity towards HaCaT and THP-1cell lines by MTT assay. The uptake of nanogel by HaCaT cell lines was confirmed by fluorescent microscopy. CLCNG at 0.35mg/ml exhibited significant anti-inflammatory activity with an average of 65% and 70% inhibition in COX and LOX activities expressed in THP-1 cells. In vitro skin permeation studies revealed the increased transdermal flux with fragmented stratum corneum and loosened epidermal layers in CLCNG treated samples, compared with control drug solution. The in vivo anti-psoriatic studies done on imiquimod model confirmed the potential benefits of the nanogel for the topical delivery of clobetasol in psoriasis.

Acitretin and aloe-emodin loaded chitin nanogel for the treatment of psoriasis.

The present study focuses on the development of an effective topical nanogel formulation of two anti-psoriatic drugs; Acitretin (Act) and Aloe-emodin (AE) using natural polymer chitin. Simple regeneration chemistry was used to prepare Chitin Nanogel Systems (CNGs). The developed control chitin (CNGs) nanogels, acitretin loaded chitin nanogels (ActCNGs) and aloe-emodin loaded chitin nanogels (AECNGs) were characterized by DLS, SEM, FTIR, XRD and TG-DTA. The systems were found to be spherical in shape with a size range of 98±10, 138±8 and 238±6nm having zeta potential values of +28±3, +27±3 and +25±6mV for CNGs, ActCNGs and AECNGs respectively. The in vitro haemolysis assay revealed that all the nanogel systems are blood compatible. The systems exhibited higher swelling and release at acidic pH. The ex vivo skin permeation studies using porcine skin confirmed the higher deposition of the systems at epidermal and dermal layers, which was confirmed further by fluorescent imaging. The in vivo anti-psoriatic activity study using Perry's mouse tail model and skin safety studies confirmed the potential benefit of the system for topical delivery of acitretin and aloe-emodin in psoriasis.