Neuromodulation with low-intensity pulsed ultrasound (Lipus) combined with curcumin-gold nanoparticles (Cur-AuNPs) in an Alzheimer's disease model
Laura de Roch Casagrande, Eduarda Behenck Medeiros, Ligia Milanez Venturini, Rubya Pereira Zaccaron, Camila da Costa, João Vitor Silvano Bittencourt, Henrique Borba Modolon, Adrielly Vargas Lidio, Sabrina Arcaro, Josiane Budni, Yaodong Gu, Anand Thirupathi, Paulo Cesar Lock Silveira
Drug Delivery 2025 · 10.1080/10717544.2025.2577826
Abstract
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that requires innovative therapeutic strategies. This is the first study to evaluate the synergistic effects of LIPUS and CUR-AuNPs in an AD model, which aimed to investigate the effects of these therapies on learning, memory and neuroinflammation in mice with β -amyloid peptide (βA1-42)-induced AD. Sixty mice were divided into five groups: control, βA1-42, βA1-42 + LIPUS, βA1-42 + CUR-AuNPs, and βA1-42 + LIPUS + CUR-AuNPs. Treatments began 24 hours after induction and continued for 17 days using intranasal CUR-AuNPs (25 μg/mL) and transcranial LIPUS (0.8 W/cm², 1 MHz). The results demonstrated that the isolated therapies reversed memory deficits in the Y-maze and radial maze tests. However, the combined therapy group was able to reverse these deficits only in the radial maze. Electron microscopy confirmed the ability of CUR-AuNPs to cross the blood‒brain barrier, especially in the combined group, and no liver toxicity was observed. All the treated groups presented increased BDNF in the hippocampus and cortex. IL-1β and IL-6 levels are reduced in the cortex, while IL-1β and TNF- α levels are decreased in the hippocampus. IL-10 increased only in the hippocampus, while GSH levels increased in both regions. Combination therapy also reduced nitrite concentrations in the hippocampus and cortex and NFκB expression in the hippocampus. APP expression decreased exclusively in the LIPUS group in the hippocampus. These results suggest that although single treatments are effective, their combination enhances neuroprotective responses through the modulation of inflammation, oxidative stress, and neurotrophic signaling, suggesting promising potential for AD treatment.
Abstract via europepmc.
Exposures
Exposure 1: LIPUS to the skull, with or without Cur-AuNPs
Target: whole brain or unfocused — “the central region of the skull”
Device: other named manufacturer · Imbramed Company, Brazil ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,000 | ✓✓✓ |
| Pulse duration (ms) | 5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 100 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 360 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 0.8 | ✓✓✓ |
Unfocused collimated physiotherapy-type transducer moved in circular motions over the skull with saline/Carbopol gel under isoflurane; intensity 0.8 W/cm2 (type of intensity not stated); 6 min per animal per session for 17 days (every 24 h per one passage, every 48 h per another); sham animals were anaesthetised only.
Flags from extraction
n_subjects— Total of 60 mice in five groups of 12; only the LIPUS groups (groups 3 and 5) were sonicated, number exposed not stated as a total.exposures[0].unspecified_domain— Intensity 0.8 W/cm2 is stated without saying whether Isppa or Ispta or domain; left null.n_sessions_per_subject— Schedule is inconsistent: 'every 24 hours ... over 2 weeks' versus 'every 48 hours' over 17 days.sham_type— Control animals were only anaesthetised (no transducer application described); coded other.exposures[0].timing.sonication_duration_s— Text also describes '6-minute pulses'; 6 min per animal per session recorded as 360 s.exposures[0].target.terms— Unfocused skull-level treatment; no brain target stated.