Neurodegenerative disorders: Mechanisms of degeneration and therapeutic approaches with their clinical relevance.

Neurodegenerative disorders (NDs) are expected to pose a significant challenge for both medicine and public health in the upcoming years due to global demographic changes. NDs are mainly represented by degeneration/loss of neurons, which is primarily accountable for severe mental illness. This neuronal degeneration leads to many neuropsychiatric problems and permanent disability in an individual. Moreover, the tight junction of the brain, blood-brain barrier (BBB)has a protective feature, functioning as a biological barrier that can prevent medicines, toxins, and foreign substances from entering the brain. However, delivering any medicinal agent to the brain in NDs (i.e., Multiple sclerosis, Alzheimer's, Parkinson's, etc.) is enormously challenging. There are many approved therapies to address NDs, but most of them only help treat the associated manifestations. The available therapies have failed to control the progression of NDs due to certain factors, i.e., BBB and drug-associated undesirable effects. NDs have extremely complex pathology, with many pathogenic mechanisms involved in the initiation and progression; thereby, a limited survival rate has been observed in ND patients. Hence, understanding the exact mechanism behind NDs is crucial to developing alternative approaches for improving ND patients' survival rates. Thus, the present review sheds light on different cellular mechanisms involved in NDs and novel therapeutic approaches with their clinical relevance, which will assist researchers in developing alternate strategies to address the limitations of conventional ND therapies. The current work offers the scope into the near future to improve the therapeutic approach of NDs.

Mucoadhesive chitosan-poly (lactic-co-glycolic acid) nanoparticles for intranasal delivery of quetiapine - Development & characterization in physiologically relevant 3D tissue models.

Quetiapine hemifumarate (QF) delivery to the CNS via conventional formulations is challenging due to poor solubility and lower oral bioavailability (9 %). Similarly, many other second-generation antipsychotics, such as olanzapine, clozapine, and paliperidone, have also shown low oral bioavailability of <50 %. Hence, the present work was intended to formulate QF-loaded biodegradable PLGA-NPs with appropriate surface charge modification through poloxamer-chitosan and investigate its targeting potential on RPMI-2650 cell lines to overcome the limitations of conventional therapies. QF-loaded poloxamer-chitosan-PLGA in-situ gel (QF-PLGA-ISG) was designed using emulsification and solvent evaporation techniques. Developed QF-PLGA-ISG were subjected to evaluation for particle size, PDI, zeta potential, ex-vivo mucoadhesion, entrapment efficiency (%EE), and drug loading, which revealed 162.2 nm, 0.124, +20.5 mV, 52.4 g, 77.5 %, and 9.7 %, respectively. Additionally, QF-PLGA formulation showed >90 % release within 12 h compared to 80 % of QF-suspension, demonstrating that the surfactant with chitosan-poloxamer polymers could sustainably release medicine across the membrane. Ex-vivo hemolysis study proved that developed PLGA nanoparticles did not cause any hemolysis compared to negative control. Further, in-vitro cellular uptake and transepithelial permeation were assessed using the RPMI-2650 nasal epithelial cell line. QF-PLGA-ISG not only improved intracellular uptake but also demonstrated a 1.5-2-fold increase in QF transport across RPMI-2650 epithelial monolayer. Further studies in the EpiNasal™ 3D nasal tissue model confirmed the safety and efficacy of the developed QF-PLGA-ISG formulation with up to a 4-fold increase in transport compared to plain QF after 4 h. Additionally, histological reports demonstrated the safety of optimized formulation. Finally, favorable outcomes of IN QF-PLGA-ISG formulation could provide a novel platform for safe and effective delivery of QF in schizophrenic patients.

Potential biomaterials and experimental animal models for inventing new drug delivery approaches in the neurodegenerative disorder: Multiple sclerosis.

The tight junction of endothelial cells in the central nervous system (CNS) has an ideal characteristic, acting as a biological barrier that can securely regulate the movement of molecules in the brain. Tightly closed astrocyte cell junctions on blood capillaries are the blood-brain barrier (BBB). This biological barrier prohibits the entry of polar drugs, cells, and ions, which protect the brain from harmful toxins. However, delivering any therapeutic agent to the brain in neurodegenerative disorders (i.e., schizophrenia, multiple sclerosis, etc.) is extremely difficult. Active immune responses such as microglia, astrocytes, and lymphocytes cross the BBB and attack the nerve cells, which causes the demyelination of neurons. Therefore, there is a hindrance in transmitting electrical signals properly, resulting in blindness, paralysis, and neuropsychiatric problems. The main objective of this article is to shed light on the performance of biomaterials, which will help researchers to create nanocarriers that can cross the blood-brain barrier and achieve a therapeutic concentration of drugs in the CNS of patients with multiple sclerosis (MS). The present review focuses on the importance of biomaterials with diagnostic and therapeutic efficacy that can help enhance multiple sclerosis therapeutic potential. Currently, the development of MS in animal models is limited by immune responses, which prevent MS induction in healthy animals. Therefore, this article also showcases animal models currently used for treating MS. A future advance in developing a novel effective strategy for treating MS is now a potential area of research.

Nanostructured lipid carriers engineered for intranasal delivery of teriflunomide in multiple sclerosis: optimization and in vivo studies.

BACKGROUND: Multiple sclerosis (MS) is one of the most severe autoimmune disorder of the central nervous system (CNS). OBJECTIVE: The present research work was aimed to formulate and investigate teriflunomide (TFM)-loaded intranasal (i.n.) nanostructured lipid carriers (NLC) for the treatment of multiple sclerosis (MS). METHODS: The TFM-loaded NLC (TFM-NLC) nanoparticles were prepared by melt emulsification ultrasonication method using biodegradable and biocompatible polymers. The Box-Behnken statistical design was applied to optimize the formulation. The optimized NLC formulation was subjected to evaluate for particle size, entrapment efficiency (%), in vitro and ex vivo permeation. The safety and efficacy of optimized formulations were demonstrated using pharmacodynamic, subacute toxicity and hepatotoxicity data. RESULTS: Experimental data demonstrated that optimized NLC formulation (F17) showed significant size (99.82 ± 1.36 nm), zeta potential (-22.29 ± 1.8 mV) and % entrapment efficiency (83.39 ± 1.24%). Alternatively, ex vivo permeation of TFM mucoadhesive NLC (TFM-MNLC) and TFM-NLC was observed 830 ± 7.6 and 651 ± 9.8 µg/cm2, respectively. Whereas, TFM-MNLC shows around 2.0-folds more Jss than the TFM-NLC. Finally, TFM-MNLC (i.n.) formulation produced the rapid remyelination in cuprizone-treated animals and decreases the number of entries in open compartment of EPM when compared with negative control and TFM-NLC (oral) animals. Simultaneously, the nanoformulation did not reflect any gross changes in hepatic biomarkers and subacute toxicity when compared with control. CONCLUSIONS: Hence it can be inferred that the nose-to-brain delivery of TFM-MNLC can be considered as effective and safe delivery for brain disorders.

Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies.

Potential risk of agranulocytosis is one of the drug-induced adverse effects of the second-generation antipsychotic agents. The present investigation aimed to formulate and investigate olanzapine (OLZ)-loaded nanostructured lipid carriers (OLZ-NLCs) via intranasal (i.n.) route. The NLC was prepared by melt emulsification method and optimized by Box-Behnken design. Mucoadhesive NLC was prepared by using 0.4% Carbopol 974P (OLZ-MNLC (C)) and the combination of 17% poloxamer 407 and 0.3% of HPMC K4M (OLZ-MNLC (P+H)). The particle size, zeta potential, and entrapment efficiency were found to be 88.95 nm ± 1.7 nm, - 22.62 mV ± 1.9 mV, and 88.94% ± 3.9%, respectively. Ex vivo permeation of OLZ-NLC, OLZ-MNLC (P+H), and OLZ-MNLC (C) was found to be 545.12 µg/cm2 ± 12.8 µg/cm2, 940.02 µg/cm2 ± 15.5 µg/cm2, and 820.10 µg/cm2 ± 11.3 µg/cm2, respectively, whereas the OLZ-MNLC (P+H) formulation showed rapid drug permeation than the OLZ-NLC and OLZ-MNLC (C) formulations. The OLZ-MNLC (P+H) formulation was shown to have 13.57- and 27.64-fold more Jss than the OLZ-MNLC (C) and OLZ-NLC formulations. The OLZ nanoformulations showed sustained release of up to 8 h. Finally, the brain Cmax of technetium-99m (99mTc)-OLZ-MNLC (i.n.) and 99mTc-OLZ-NLC (i.v.) was found to be 936 ng and 235 ng, respectively, whereas the Cmax of i.n. administration was increased 3.98-fold more than the Cmax of i.v. administration. The in vivo hematological study of OLZ-MNLC (P+H) confirmed that the i.n. formulation did not reflect any variation in leukocyte, RBC and platelet counts. Hence, it can be concluded that the nose-to-brain delivery of OLZ-MNLC (P+H) can be considered as an effective and safe delivery for CNS disorders.