The N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline-Enriched Methanol Fraction from Sideroxylon obtusifolium Shows an Anticonvulsant Activity Associated with its Anti-inflammatory/Antioxidant Actions

Abstract

Epilepsy is a neurological disorder characterized by recurrent seizures, resulting from excessive neuronal discharges. Sideroxylon obtusifolium is used in Brazil for its anti-inflammatory/antioxidant properties, known to be involved with epilepsy. The anticonvulsant effects of the methanol fraction from S. obtusifolium leaves, rich in N-methyl-(2S,4R)-trans-4-hydroxy-L-proline, were investigated on pilocarpine- and pentylenetetrazole-induced convulsion models. Mice were pretreated with N-methyl-(2S,4R)-trans-4-hydroxy-L-proline (50, 100, 200 mg/kg, p.o.) and, 1 h later, by pilocarpine (400 mg/kg, i.p.) or pentylenetetrazole (80 mg/kg, i.p.). The animals were observed for latency to the first convulsion and latency to death. Immediately after death, brain areas from the pilocarpine groups were harvested for biochemical measurements. The latency to the first convulsion and latency to death increased after N-methyl-(2S,4R)-trans-4-hydroxy-L-proline treatment compared with the pilocarpine- or pentylenetetrazole-only groups. In both convulsion models, sodium valproate (reference drug) was used as a positive control. Additionally, the decreases in striatal dopamine and 3,4-dihydroxyphenylacetic acid contents observed in the pilocarpine-only group were partially prevented in the N-methyl-(2S,4R)-trans-4-hydroxy-L-proline-treated groups. While brain gamma-aminobutyric acid and glutamate contents decreased and increased, respectively, after pilocarpine only, these changes were also prevented by N-methyl-(2S,4R)-trans-4-hydroxy-L-proline. Similarly, N-methyl-(2S,4R)-trans-4-hydroxy-L-proline reduced the brain oxidative stress by decreasing the levels of nitrite and lipid peroxidation and increasing the glutathione content of the pilocarpine-only group. The increases in hippocampal expressions for interleukin 6, interferon-gamma, and glial fibrillary acidic protein, after pilocarpine only, were decreased to normal levels by N-methyl-(2S,4R)-trans-4-hydroxy-L-proline. In conclusion, the study showed significant anticonvulsant effects for N-methyl-(2S,4R)-trans-4-hydroxy-L-proline, probably related to its anti-inflammatory/antioxidant properties. N-Methyl-(2S,4R)-trans-4-hydroxy-L-proline effects were potentiated by VPA (sodium valproate), thus it may also interact with the GABAergic system, as we had recently shown.

Development of curcumin-loaded liposomes in lysine–collagen hydrogel for surgical wound healing

“…In another study by de Aquino et al, 10% Methyl-(2R, 4R)-trans-4-hydroxy-L-proline gel was formulated and used to treat wounds induced on mice. It was observed that while collagen deposition increased on days 7 and 12, only 58% wound reduction was observed by day 12 suggesting that the effect of hydroxy-L-proline in enhancing wound contraction may not be as pronounced as that of lysine in this current study [40]. Collagen is also known to increase the tensile strength of the tissue during healing at the wound area [39].…”

“…The number of microvessels in the granulation tissue and the thickness of the central region of the epidermis to dermis indicate the depth of structural wound healing taking place as formation of microvessels is necessary for vascular function at the wound site. Formulations F1-F3 showed higher numbers of microvessels and more thickness of the central region of the epidermis and the dermis compared to the control [40][41][42].…”

Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-β-Induced Alzheimer’s Disease Mouse Model

“…The previously reported effects of this compound include anti-oxidant, anti-inflammatory, anti-nociceptive, as well as hypoglycemic activity [15]. In addition, the anti-convulsing effects of the L-proline derivative were evaluated in different models of PTZ-and Piloinduced epilepsy in mice models [16]. Furthermore, the nanoemulsion of Sideroxylon obtusifolium is used to treat schistosomiasis [17].…”

N-Methyl-(2S,4R)-trans-4-hydroxy-L-proline isolated Sideroxylon obtusifolium attenuates TPA-induced irritant contact dermatitis in mice

“…Extracts and fractions enriched in N-methyl-(2S,4R)-trans-4-hydroxy-L-proline (NMP), a constituent of S. obtusifolium leaves, have demonstrated biological activities as antioxidants (Aquino et al 2020) and systemic anti-inflammatories (Aquino et al 2017(Aquino et al , 2019(Aquino et al , 2020. NMP is a derivative of L-proline, an amino acid commonly used as a dietary supplement to stimulate collagen synthesis in the body (Vitagliano et al 2001).…”