Neuroprotective Potential of 6-O-(3-Hexadecyloxy-2-Hydroxypropyl)-Piperine-Nanoparticles in a Rat Model of Cerebral Ischemia-Reperfusion Injury

Abstract

Purpose Piperine is an alkaloid found in black pepper (piper nigrum) responsible for pungent smelling, potential therapeutic benefits. It has several significant biological properties, such as bioavailability enhancer, therapeutic potential, low water solubility, pharmakinetic properties, cardiovascular benefits, and neuroprotective effects. In a rodent model of transient focal cerebral ischemia-reperfusion injury (TFCIRI), piperine has been demonstrated to have a protective effect on the brain. Methods The present study was designed to prepare 6-O-(3-hexadecyloxy-2-hydroxypropyl dextran (HDD)--Piperine-Nanoparticles (HDD-PIP-NPs), its physicochemical characterization and neuroprotective potential against TFCIRI. The piperine was encapsulated in self-assembled 6-O-(3-hexadecyloxy-2-hydroxypropyl)-dextran (HDD) nanoparticles (HDD-PIP-NPs). HDD-PIP-NPs were characterized for their drug loading, entrapment efficiency, particle size, surface morphology, and in-vitro drug release profile. Results Plasma pharmacokinetics (C_max (4.71 ± 0.77), T_max (60 min), t_1/2 (449.19 ± 98.02), UAC_{1 − infinite} (641.62 ± 54.01), and UAC_{1 − 360} (641.62 ± 54.01)) brain distribution profile of PIP in cerebrum, cerebellum and cortical region, and the neuroprotective potential of HDD-PIP-NPs have been characterised in rat model of TFCIRI. HDD-PIP-NPs (14, 28, and 56 mg/kg) was administered orally after 1h onset of TFCIRI. HDD-PIP-NPs chemical synthesis and its biochemical and biophysical characterization have been done. The percentage decreased infarction (~ 52.52%) of orally administered HDD-PIP-NPs (56 mg/kg) is ameliorated in rat model of TFCIRI. Physiological parameters such as CBF (~ 201.23), pCO₂ (~ 38.55 mmHg), pO₂ (~ 128.42 mmHg) and rectal temperature (~ 36.9ºC) was recorded the 56mg/kg oral treatment. Neurological deficit score recorded after the 24h, 48h and 72h of reperfusion injury. Brain penetration studies and bioavailability of PIP estimated in male Charles foster albino rats. The results indicated that HDD-PIP-NPs treatment significantly decreased the percentage of infarction, percentage brain water content and neurological deficit scores in dose dependent manner. Conclusion These findings suggest that piperine (PIP) possesses significant neuroprotective potential. Its nano-formulation, HDD-PIP-NPs, has shown enhanced plasma and brain pharmacokinetics, leading to improved neurological outcomes following transient focal cerebral ischemia-reperfusion injury (TFCIRI) in rats. HDD-PIP-NPs could potentially be useful for neuroprotective interventions against various neurological disorders.