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Niosomal Formulation of a Lipoyl-Carnosine Derivative Targeting TRPA1 Channels in Brain

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Niosomal Formulation of a Lipoyl-Carnosine Derivative Targeting TRPA1 Channels in Brain

Francesca Maestrelli et al. Pharmaceutics.

Abstract

The transient receptor potential akyrin type-1 (TRPA1) is a non-selective cation channel playing a pivotal role in pain sensation and neurogenic inflammation. TRPA1 channels expressed in the central nervous system (CNS) have a critical role in the modulation of cortical spreading depression (CSD), which is a key pathophysiological basis of migraine pain. ADM_09 is a recently developed lipoic acid-based TRPA1 antagonist that is able to revert oxaliplatin-induced neuropathic pain and inflammatory trigeminal allodynia. In this context, aiming at developing drugs that are able to target TRPA1 channels in the CNS and promote an antioxidant effect, permeability across the blood-brain barrier (BBB) represents a central issue. Niosomes are nanovesicles that can be functionalized with specific ligands selectively recognized by transporters expressed on the BBB. In this work, the activity of ADM_09 on neocortex cultures was studied, and an efficient formulation to cross the BBB was developed with the aim of increasing the concentration of ADM_09 into the brain and selectively delivering it to the CNS rapidly after parenteral administration.

Keywords: TRPA1 antagonist; blood brain barrier; cortical spreading depression; niosomes.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of lipoic acid, carnosine, and ADM_09.
Figure 2
Figure 2
(A) Data points represent the average number of spikes per neuron, normalized to the average value measured in control extracellular solution (control), for 2.5 h. Next, ADM_09 was added at the indicated concentrations (µg/mL). Each concentration was left for 15 min. After the drug was removed (recovery), excitability returned to the control values within 1 h. Each data point for control and recovery represents 1 h recording, as indicated. Red squares: excitatory cluster; black circles: inhibitory cluster. (B) Same as A, but giving the average inter-burst interval between network bursts (NB-IBI). (C) Mean spike rate in control and ADM_09 (12.4 µg/mL) for the excitatory (red) and the inhibitory cluster (gray). * p < 0.05.
Figure 3
Figure 3
TEM micrographs of NIO (A) and NIO ADM_09 (B) and the corresponding magnification of NIO (C) and NIO ADM_09 (D).
Figure 4
Figure 4
Particle size (nm) of NIO (green) and NIO ADM_09 (red) during the stability test conducted for 8 weeks at 5 °C (A), 25 °C (B), and 37 °C (C) (75% RH). RH: relative humidity.
Figure 5
Figure 5
Drug release of ADM_09 from solution and loaded niosomes (NIO ADM_09).
Figure 6
Figure 6
Citotoxicity studies at different concentrations of ADM_09 (0.14 and 0.07 mg/mL), empty noisomes (NIO), and loaded niosomes (NIO ADM_09) for 2h (A) and 24 h (B). ** p < 0.05.
Figure 7
Figure 7
hCMEC/D3 apparent permeability coefficient (Papp) of free drug (ADM_09 blue) and loaded in niosomes (NIO ADM_09 green) after incubation of 30, 60, and 120 min. ** p < 0.05.

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