Intranasal Administration of Undifferentiated Oligodendrocyte Lineage Cells as a Potential Approach to Deliver Oligodendrocyte Precursor Cells into Brain

Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

​​Differential Disease Resistance of Indian Native Chicken Breeds to Experimental P. multocida Infection

Background: Native chicken breeds are considered more disease tolerant than exotic chicken breeds especially for the bacterial diseases. Aseel, Ghagus and Vanaraja chicken breeds/ variety were evaluated for the disease tolerance/susceptibility pattern after experimental infection with P. multocida A:1 isolate. Methods: A total of 72 birds of three breeds viz., Aseel, Ghagus and Vanaraja (n=24 each) were divided into three groups. The birds were inoculated with 2.5x106 CFU/ml of virulent Pasteurella multocida A:1 isolate through intraperitoneal (I/P) and intranasal (I/N) routes at 12 weeks of age. Clinical signs, morbidity, mortality rates and lesions were observed in the infected birds. Result: The mortality rates were 83.3% in Assel breed against 100% in both Ghagus and Vanaraja breed in intraperitoneally infected groups. Upon intranasal infection, the mortality was 83.3% in Assel and Vanaraja breed against 100% in Ghagus breed. Aseel birds showed significantly better survivability and longer death time than Ghagus breed upon experimental infection with Pasteureall multocida A:1 isolate. Vanaraja breed showed tolerance comparable to Aseel in experimental infection via intranasal route.

Intranasal Dexamethasone: a New Clinical Trial For The Control of Inflammation and Neuroinflammation in Covid-19 Patients

COVID-19 has produced more than 176 million infected individuals and almost 3.2 million deaths worldwide. The infection results in a dysregulated systemic inflammation, multi-organ dysfunction, and critical illness. Cells of the central nervous system (CNS) are also affected triggering a dysregulated neuroinflammatory response.Low doses of glucocorticoids (GCs) orally or intravenously administered has been proved to reduce mortality of moderate and severe COVID-19 patients. However, low doses administered by those routes do not reach therapeutic levels in the CNS. In contrast, if dexamethasone is administered by the intranasal route can result in therapeutic doses in the CNS even at low doses of the GC. Methods: This is an approved multicentric randomized controlled protocol to compare the effectiveness of low doses of intranasal dexamethasone versus intravenous administered in adult moderate and severe COVID-19 patients. The protocol is conducted in five health institutions in Mexico City. A total of 120 patients will be randomized in two groups (intravenous vs intranasal) at 1:1 ratio, both groups will be treated with these dexamethasone schemes for 10 days. The primary outcome of the study will be clinical improvement, defined as a statistically significant higher reduction in the NEWS-2 score in intranasally versus intravenously dexamethasone treated patients. The second outcome will be the reduction in mortality during hospitalization. Conclusions: This protocol is currently undertaken to improve the efficacy of the standard therapeutic dexamethasone regimen for moderate and severe COVID-19 patients. Trial registration: ClinicalTrials.gov identifier: NCT04513184 Registered November 12, 2020 and was approved by COFEPRIS with identifier DI/20/407/04/36. People are currently being recruited.

DEVELOPMENT OF RIVASTIGMINE LOADED SELF ASSEMBLED NANOSTRUCTURES OF NONIONIC SURFACTANTS FOR BRAIN DELIVERY

Objective: Aim of the study is to develop rivastigmine-loaded niosomal in situ gel via the intranasal route to the brain by crossing the Blood-Brain Barrier. For the treatment of Alzheimer’s disease, it provides a speedy onset of action, a faster therapeutic effect, avoidance of the first-pass metabolism, and enhanced bioavailability. Methods: Rivastigmine niosomal in situ nasal gel was developed, refined and tested with the goal of delivering the medicine to the brain via the intranasal route Rivastigmine niosomes were formulated by thin-film hydration technique, optimized using (32) factorial design and characterized for its physicochemical parameters. Rivastigmine-loaded niosomes were further incorporated into Carbopal-934P and HPMC-K4M liquid gelling system to form in situ nasal gel. The resulting solution was evaluated for several parameters including, viscosity at pH 5 and pH 6, gelling capacity and gelling time. Results: Optimized best formulation containing span 60 (A) and cholesterol (B) with (1:0.5) ratio identified from the model developed from Design-Expert®12 software, exhibited Entrapment efficiency (76.5±0.23%), particle size (933.4±0.14 nm), in vitro drug release maximum (68.94±0.26%) at 8th hour and further studied for its characteristics by SEM and TEM showed stable vesicles. Polynomial equations of Y1, Y2, and Y3 were conducted and ANOVA results showed a significant impact (p<0.05) on three levels. In vivo perfusion studies using rat model showed, the niosomes developed has good perfusion compared to pure drug with 27.2% of drug absorption in the brain at the end of 3 h. In vitro permeation of Rivastigmine through the dialysis membrane showed that 60.74% w/w drug permeated after 8 h. The formation of stable vesicles was proved by Zeta potential measurements and SEM analysis. Conclusion: Optimized formulation had greater perfusion and was expected to have a good bioavailability compared to conventional other drug delivery systems.

Intranasal Drug Delivery: Novel Delivery Route for Management of Parkinson’s and Depression Neurological Disorders

Neurological disorders are increasing worldwide due to the rapidly aging population, which increases healthcare costs. Drug delivery to the brain is challenging because of the brain's anatomy, and orally administered drugsare mostly unable to cross BBB. Intranasal (Nose to Brain) administration of drugs is one novel approach to address this challenge. Intranasal delivery has appeared to evade the blood-brain barrier (BBB) and deliver the drug into the CNS at a higher rate and degree than another traditional route. Transport of drugs from the nasal cavity to the brain along with olfactory and trigeminal nerves. The purpose of this review is drug delivery by the intranasal route for treating neurological disorders like Parkinson’s and depression because drug delivery by other routes is unable to cross BBB. Still, delivery through the intranasal route by using the nanotechnology approach is possible to deliver the drug directly to CNS.

Intranasal vaccine from whole Leishmania donovani antigens provides protection and induces specific immune response against visceral leishmaniasis

Visceral leishmaniasis is a protozoan disease associated with high fatality rate in developing countries. Although the drug pipeline is constantly improving, available treatments are costly and live-threatening side effects are not uncommon. Moreover, an approved vaccine against human leishmaniasis does not exist yet. Using whole antigens from Leishmania donovani promastigotes (LdAg), we investigated the protective potential of a novel adjuvant-free vaccine strategy. Immunization of mice with LdAg via the intradermal or the intranasal route prior to infection decreases the parasitic burden in primary affected internal organs, including the liver, spleen, and bone marrow. Interestingly, the intranasal route is more efficient than the intradermal route, leading to better parasite clearance and remarkable induction of adaptive immune cells, notably the helper and cytotoxic T cells. In vitro restimulation experiments with Leishmania antigens led to significant IFN-γ secretion by splenocytes; therefore, exemplifying specificity of the adaptive immune response. To improve mucosal delivery and the immunogenic aspects of our vaccine strategy, we used polysaccharide-based nanoparticles (NP) that carry the antigens. The NP-LdAg formulation is remarkably taken up by dendritic cells and induces their maturation in vitro, as revealed by the increased expression of CD80, CD86 and MHC II. Intranasal immunization with NP-LdAg does not improve the parasite clearance in our experimental timeline; however, it does increase the percentage of effector and memory T helper cells in the spleen, suggesting a potential induction of long-term memory. Altogether, this study provides a simple and cost-effective vaccine strategy against visceral leishmaniasis based on LdAg administration via the intranasal route, which could be applicable to other parasitic diseases.