Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study

Kaya, Cengiz; Atalay, Yunus O.; Meydan, Bilge C.; Ustun, Yasemin B.; Koksal, Ersin; Caliskan, Sultan

doi:10.1016/j.bjane.2019.04.004

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Scientific Articles • Rev. Bras. Anestesiol. 69 (4) • Jul-Aug 2019 • https://doi.org/10.1016/j.bjane.2019.04.004 copy

Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study^☆ ☆ Preliminary data for this study were submitted as a poster presentation at the Turkish Society of Anesthesiology and Reanimation Congress, 26-30 October, 2016, Istanbul, Turkey. The randomized placebo-controlled experimental study was conducted at the Experimental Animals and Application Research Center, Samsun, Turkey.

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Abstract

Background and objectives

Intrathecal administration of non-steroidal anti-inflammatory drugs is more efficacious for post-operative pain management. Cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs like (S)-(+)-Ketoprofen, may be effective at lower intrathecal doses than parenteral ones. Preclinical safety regarding possible neurotoxicity associated with the intrathecal (S)-(+)-Ketoprofen was not evaluated. Here we analysed the neurotoxicity of intrathecally administered (S)-(+)-Ketoprofen in rats.

Methods

A randomized placebo-controlled experimental study was conducted. Sprague-Dawley rats (250-300 g) aged 12-16 weeks were randomly divided into 2 treatments [100 and 800 µg (S)-(+)-Ketoprofen] and control (sterile water) groups. Intrathecal catheters were placed via the atlantoaxial space in anesthetized rats. Pinch-toe tests, motor function evaluations and histopathological examinations of the spinal cord and nerve roots were performed at days 3, 7 and 21. Spinal cord sections were evaluated by light microscopy for the dorsal axonal funiculus vacuolation, axonal myelin loss, neuronal chromatolysis, neuritis, meningeal inflammation, adhesions, and fibrosis.

Results

Rats in all the groups exhibited normal pinch-toe testing response (score = 0) and normal gait at each observed time (motor function evaluation score = 1). Neurotoxicity was higher with treatments on days 3 and 7 than that on day 21 (2, 3, 0, p = 0.044; 2, 5, 0, p = 0.029, respectively). On day 7, the total scores reflecting neuronal damage were higher in the 800 µg group than those in the 100 µg and Control Groups (5, 3, 0, p = 0.048, respectively).

Conclusion

Intrathecal (S)-(+)-Ketoprofen caused dose-dependent neurohistopathological changes in rats on days 3 and 7 after injection, suggesting that (S)-(+)-Ketoprofen should not be intrathecally administered.

Keywords
Cyclooxygenase inhibitor; Intrathecal injection; (S)-(+)-Ketoprofen; Neurotoxicity; Inflammation

Days after intrathecal injection		Groups	Median (min-max)
3rd day (n = 9)	Pinch-toe test score^a a Pinch-toe test scores were graded on a 4 point scale as follows: 0, normal response with strong vocalization, reflexive limb withdrawal immediately after pinching, and biting of forceps within 6 s of the hind limb being pinched; 1, mildly impaired response; 2, moderately impaired response and 3, no response. Scores of 1 and higher are considered abnormal and indicative of motor and sensory nerve damage.	Group C	0 (0-0)
		Group 1	0 (0-0)
		Group 2	0 (0-0)
	Motor function evaluation score^b b Motor function scores were graded on a 4 point scale as follows: 1, normal gait with no motor paresis; 2, normal gait with mild irregularity of the hind limbs, such as plantar flexion of the toes; 3, mildly disordered gait and/or inversion of the hind paw and 4, incorrect foot position with significant limping. Scores of 2 and higher were considered indicative of motor nerve injury. Group C (Control Group): 20 µL of sterile water. Group 1: 100 µg (S)-(+)-Ketoprofen 2.5 µL mixture + 17.5 µL of sterile water. Group 2: 800 µg (S)-(+)-Ketoprofen (20 µL mixture).	Group C	1 (1-1)
		Group 1	1 (1-1)
		Group 2	1 (1-1)
7th day (n = 9)	Pinch-toe test score	Group C	0 (0-0)
		Group 1	0 (0-0)
		Group 2	0 (0-0)
	Motor function evaluation score	Group C	1 (1-1)
		Group 1	1 (1-1)
		Group 2	1 (1-1)
21st day (n = 9)	Pinch-toe test score	Group C	0 (0-0)
		Group 1	0 (0-0)
		Group 2	0 (0-0)
	Motor function evaluation score	Group C	1 (1-1)
		Group 1	1 (1-1)
		Group 2	1 (1-1)

	Days after intrathecal injection	Median (min-max)	p-Value
Group C (n = 9)	3rd day	0 (0-1)	0.87
	7th day	0 (0-1)
	21st day	2 (1-2)
Group 1 (n = 9)	3rd day	2 (1-3)	0.044
	7th day	3 (2-5)
	21st day	0^a a p < 0.05 versus corresponding data of days 3 and 7. Total score was graded from 0 to 6 (0 = minimum, 6 = maximum). Group C (Control Group): 20 µL of sterile water. Group 1: 100 µg (S)-(+)-Ketoprofen 2.5 µL mixture + 17.5 µL of sterile water. Group 2: 800 µg (S)-(+)-Ketoprofen 20 µL mixture. (0-0)
Group 2 (n = 9)	3rd day	2 (2-3)	0.029
	7th day	5 (3-5)
	21st day	0^a a p < 0.05 versus corresponding data of days 3 and 7. Total score was graded from 0 to 6 (0 = minimum, 6 = maximum). Group C (Control Group): 20 µL of sterile water. Group 1: 100 µg (S)-(+)-Ketoprofen 2.5 µL mixture + 17.5 µL of sterile water. Group 2: 800 µg (S)-(+)-Ketoprofen 20 µL mixture. (0-1)

	Type of damage	Days after intrathecal injection	Median (min-max)	p-Value
Group C (n = 9)	Meningeal	3rd day	0 (0-1)	0.67
		7th day	1 (0-1)
		21st day	0 (0-1)
	Axonal	3rd day	1 (0-1)	0.67
		7th day	1 (0-1)
		21st day	1 (0-1)
	Neuronal	3rd day	0 (0-0)	0.64
		7th day	1 (0-1)
		21st day	1 (0-1)
Group 1 (n = 9)	Meningeal	3rd day	0 (0-0)	0.20
		7th day	0 (0-2)
		21st day	2 (0-2)
	Axonal	3rd day	1 (0-1)	1
		7th day	1 (0-2)
		21st day	2 (0-2)
	Neuronal	3rd day	1 (0-1)	1
		7th day	1 (0-1)
		21st day	1 (0-1)
Group 2 (n = 9)	Meningeal	3rd day	0 (0-1)	1
		7th day	0 (0-1)
		21st day	1 (0-1)
	Axonal	3rd day	0 (0-1)	0.56
		7th day	0 (0-0)
		21st day	0 (0-1)
	Neuronal	3rd day	0 (0-0)	0.64
		7th day	0 (0-0)
		21st day	0 (0-0)

Days after intrathecal injection	Type of damage	Groups	Median (min-max)	p-Value
3rd day (n = 9)	Meningeal	Group C	0 (0-1)	0.202
		Group 1	0 (0-0)
		Group 2	0 (0-1)
	Axonal	Group C	1 (0-1)	0.396
		Group 1	1 (0-1)
		Group 2	0 (0-1)
	Neuronal	Group C	0 (0-0)	0.801
		Group 1	1 (0-1)
		Group 2	0 (0-0)
7th day (n = 9)	Meningeal	Group C	1 (0-1)	0.102
		Group 1	0 (0-2)
		Group 2	0 (0-1)
	Axonal	Group C	1 (0-1)	0.202
		Group 1	1 (0-2)
		Group 2	0 (0-0)
	Neuronal	Group C	1 (0-1)	0.202
		Group 1	1 (0-1)
		Group 2	0 (0-0)
21st day (n = 9)	Meningeal	Group C	0 (0-1)	0.670
		Group 1	2 (0-2)
		Group 2	1 (0-1)
	Axonal	Group C	1 (0-1)	0.396
		Group 1	2 (0-2)
		Group 2	0 (0-1)
	Neuronal	Group C	1 (0-1)	0.211
		Group 1	1 (0-1)
		Group 2	0 (0-0)

Days after intrathecal injection		Groups	Median (min-max)	p-Value
3rd day (n = 9)	Total score	Group C	0 (0-1)	0.72
		Group 1	2 (1-3)
		Group 2	2 (2-3)
7th day (n = 9)	Total score	Group C	0 (0-1)	0.048
		Group 1	3 (2-5)
		Group 2	5^a a p < 0.05 vs. corresponding data of Group C and Group 1. (3-5)
21st day (n = 9)	Total score	Group C	1 (0-1)	0.044
		Group 1	0^b b p < 0.05 vs. corresponding data of Group C and Group 2. Total score was graded from 0 to 6 (0 = minimum, 6 = maximum). Group C (Control Group): 20 µL of sterile water. Group 1: 100 µg (S)-(+)-Ketoprofen 2.5 µL mixture + 17.5 µL of sterile water. Group 2: 800 µg (S)-(+)-Ketoprofen 20 µL mixture. (0-0)
		Group 2	0 (0-1)

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[1] * Corresponding author. E-mail:cengiz.kaya@omu.edu.tr (C. Kaya).