Abstract
Purpose: To prepare hydrogels loaded with epicatechin, a strong antioxidant, anti-inflammatory, and neuroprotective tea flavonoid, and characterise them in situ as a vehicle for prolonged and safer drug delivery in patients with post-traumatic spinal cord injury.Methods: Five in situ gel formulations were prepared using chitosan and evaluated in terms of their visual appearance, clarity, pH, viscosity, and in vitro drug release. In vivo anti-inflammatory activity was determined and compared with 2 % piroxicam gel as standard. Motor function activity in a rat model of spinal injury was examined comparatively with i.v. methylprednisolone as standard.Results: The N-methyl pyrrolidone solution (containing 1 % w/w epicatechin with 2 to 10 % w/w chitosan) of the in situ gel formulation had a uniform pH in the range of 4.01 ± 0.12 to 4.27 ± 0.02. High and uniform drug loading, ranging from 94.48 ± 1.28 to 98.08 ± 1.24 %, and good in vitro drug release (79.48 ± 2.84 to 96.48 ± 1.02 % after 7 days) were achieved. The in situ gel prepared from 1 % epicatechin and 2 % chitosan (E5) showed the greatest in vivo anti-inflammatory activity (60.58 % inhibition of paw oedema in standard carrageenan-induced hind rat paw oedema model, compared with 48.08 % for the standard). The gels showed significant therapeutic effectiveness against post-traumainduced spinal injury in rats. E5 elicited maximum motor activity (horizontal bar test) in the spinal injuryrat model; the rats that received E5 treatment produced an activity score of 3.62 ± 0.02 at the end of 7 days, compared with 5.0 ± 0.20 following treatment with the standard.Conclusion: In situ epicatechin-loaded gel exhibits significant neuroprotective and anti-inflammatory effects, and therefore can potentially be used for prolonged and safe drug delivery in patients with traumatic spinal cord injury.Keywords: Epicatechin, In situ gel, Chitosan, Spinal injury, Post-traumatic, Motor activity, Antiinflammatory
Highlights
Flavonoids are the largest group of bioactive polyphenols found in nature
The neuroprotective effects induced by EpC and other various green tea extracts include attenuated ischaemic brain injury and inhibition of excitotoxicity and are evidenced by improved cognitive performance and memory retention; these effects may be utilised in patients with spinal cord injury (SCI) [5,6,7,8]
The primary tissue injury leads to a cascade of adverse events, such as inflammation and apoptosis, which result in neuropathic pain, inflammation, and reversible and/or irreversible damage to the nervous system, known as secondary injury [9,10,11,12]
Summary
Flavonoids are the largest group of bioactive polyphenols found in nature. Green and black teas are the richest sources of polyphenols, flavanols and flavonols, which comprise 30 % of the dry weight of the fresh leaf. Green tea polyphenols, including EpC, reportedly exert antioxidant, anti-inflammatory, anticarcinogenic, antiviral, anti-arthritic, antibacterial, antiangiogenic, neuroprotective, and antihyperlipidemic effects These flavones induce apoptosis and cell cycle arrest in a wide array of cell lines, and protect against cerebral ischaemia [1,2]. The in vivo anti-inflammatory activity of the formulations was evaluated using the standard carrageenan-induced rat hind paw oedema model. For Groups II to V, the in situ gel formulations were injected (20 mg/kg body weight; intra venous) into the left hind paw of the rats. The standard group received intravenous (i.v.) methylprednisolone (30 mg/kg body weight) at 30 min post-injury to allow for drug release. This daily treatment was repeated for 1 week. A value of p < 0.05 was considered to indicate statistical significance
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