Development and evaluation of loperamide hydrochloride loaded chitosan nanoformulation for neurotoxic effects on mice

NMDAR (N-methyl-D-aspartate receptor) antagonist and opioid agonist can induce psychosis in rodents and humans. Loperamide hydrochloride (LH) possesses NMDAR antagonistic and opioid agonistic property but associated with more peripheral effects and limited blood brain barrier (BBB) penetration. So, it is essential to make its nanoformulation to increase BBB penetration and reduce peripheral effects. Thus, this study aimed to develop of LH encapsulated tween 80 coated chitosan nanoformulations and to optimize the formulations for targeting into brain. 3(2) full factorial design was performed to optimize the preparation to enhance the entrapment of the drug and reduce the particle size of all batches were between 189-278 nm and 80.16-89.38%, respectively. Pure drug LH (1 mg/kg, p.o) and LH loaded tween 80 coating chitosan nanoparticles (LCNP) (dose equal to 1 mg/kg LH, p.o.) were administrated in different group of animals to produce psychosis like behaviors in terms of stereotypic behaviors, hyper-locomotors activity, immobility and increased step down latency. LH and LCNP were administered orally for 15 successive days and behavioral, biochemical and histopathological alterations were studies. In mice, LCNP administration showed to induced behavioral changes similar to psychotic symptoms. However, administration of LH didn't shows significant effect in cognitive symptom. Moreover, LCNP significantly decreased GSH and GABA level and increased MDA. Histopathologically, LCNP was significant to produce perinuclear vacuolization and hyperchromatic nuclei in the brain cortex, which indicates its damaging effects on brain. Thus, the surface modified NPs (LCNP) enhanced the penetration efficacy of LH. These studies revealed that LCNP could be effective chemical model to induce psychosis with good face, predictive and construct validity.