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Purpose <p>Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by mitochondrial dysfunction, oxidative stress, and neuroinflammation, for which effective therapies remain undiscovered. In the present study, a piperine-loaded liposomal thermoresponsive hydrogel (PI-LP-G) was developed as a potential nose-to-brain delivery system, and its neuroprotective potential was evaluated in SHSY-5Y cells and SD rats with HD-like symptoms induced by 3-nitropropionic acid (3-NP).</p> Methods <p>The ethanol injection method was used to fabricate liposomes, which were then further loaded into a thermoresponsive hydrogel. Compared to the free piperine, the oxidative stress reduction and mitochondrial repolarisation potential of liposomes were estimated using DCFH-DA and JC-1 assays. Neurobehavioral assessment was utilised to assess the neuroprotective role.</p> Results <p>Piperine liposomes (PI-LPs) were optimised to get stable nanosized vesicles (109 ± 2.1&#xa0;nm) with high encapsulation efficiency (75.8 ± 1.8%) and a negative surface charge (− 32.9 mV). Solid-state and release studies confirmed molecular encapsulation and amorphisation of piperine, resulting in significantly enhanced and sustained drug release (78.62% over 24&#xa0;h) compared with free piperine (33.63%). In SH-SY5Y cells, PI-LPs exhibited superior cytocompatibility and significantly attenuated 3-NP-induced mitochondrial dysfunction, as evidenced by reduced oxidative stress and preservation of mitochondrial membrane potential. Intranasal administration of PI-LP-G in 3-NP–treated SD rats significantly improved locomotor activity, alleviated anxiety and depressive-like behaviour, and restored recognition memory, with behavioural outcomes approaching those of sham controls.</p> Conclusion <p>PI-LP-G exerts neuroprotection via mitochondrial stabilisation and reduced ROS, thereby interrupting key pathogenic pathways implicated in Huntington’s disease and warranting further translational investigation.</p> Graphical Abstract <p></p>

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Exploring Neuroprotective Activity of a Piperine Liposomal Thermogel in 3-nitropropionic Acid-Induced Huntington’s Disease Models

  • 期刊论文

  • 发表日期：

    2026年4月22日

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  • Ayush Kumar,
  • Ashish Dilip Sutar,
  • Khushboo Kumari,
  • Rahul Shukla

摘要

Purpose

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by mitochondrial dysfunction, oxidative stress, and neuroinflammation, for which effective therapies remain undiscovered. In the present study, a piperine-loaded liposomal thermoresponsive hydrogel (PI-LP-G) was developed as a potential nose-to-brain delivery system, and its neuroprotective potential was evaluated in SHSY-5Y cells and SD rats with HD-like symptoms induced by 3-nitropropionic acid (3-NP).

Methods

The ethanol injection method was used to fabricate liposomes, which were then further loaded into a thermoresponsive hydrogel. Compared to the free piperine, the oxidative stress reduction and mitochondrial repolarisation potential of liposomes were estimated using DCFH-DA and JC-1 assays. Neurobehavioral assessment was utilised to assess the neuroprotective role.

Results

Piperine liposomes (PI-LPs) were optimised to get stable nanosized vesicles (109 ± 2.1 nm) with high encapsulation efficiency (75.8 ± 1.8%) and a negative surface charge (− 32.9 mV). Solid-state and release studies confirmed molecular encapsulation and amorphisation of piperine, resulting in significantly enhanced and sustained drug release (78.62% over 24 h) compared with free piperine (33.63%). In SH-SY5Y cells, PI-LPs exhibited superior cytocompatibility and significantly attenuated 3-NP-induced mitochondrial dysfunction, as evidenced by reduced oxidative stress and preservation of mitochondrial membrane potential. Intranasal administration of PI-LP-G in 3-NP–treated SD rats significantly improved locomotor activity, alleviated anxiety and depressive-like behaviour, and restored recognition memory, with behavioural outcomes approaching those of sham controls.

Conclusion

PI-LP-G exerts neuroprotection via mitochondrial stabilisation and reduced ROS, thereby interrupting key pathogenic pathways implicated in Huntington’s disease and warranting further translational investigation.

Graphical Abstract