Download Effects of magnesium sulfate on spinal cord tissue lactate and

ORIGINAL ARTICLE
Magnesium Research 2005; 18 (3): 170-4
Experimental paper
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Effects of magnesium sulfate
on spinal cord tissue lactate
and malondialdehyde levels
after spinal cord trauma
M. Özdemir1, S
q ahika Liva Cengiz2, M. Gürbilek3, T.C. Öğün4, M.E. Üstün5
1
Orthopedics and Traumatology Department, Selcuk University, Meram Faculty of
Medicine, Konya; 2 Neurosurgery Department, Selcuk University, Meram Faculty of
Medicine, Konya; 3 Biochemistry Department, Selcuk University, Meram Faculty of
Medicine, Konya; 4 Orthopedics and Traumatology Department, Selcuk University,
Meram Faculty of Medicine, Konya; 5 Neurosurgery Department, Selcuk University,
Meram Faculty of Medicine, Konya
Correspondence: S
q. Liva Cengiz. Resident, Selcuk University, Meram Medicine Faculty, Neurosurgery Department A/5
Meram Akyokuş 42080, Konya, Turkey. Tel.: (+ 00 90) 332 223 72 82; fax: (+ 00 90) 332 223 64 28.
<[email protected]>
Abstract. Objective. In the present study, the effects of magnesium sulfate (MgSO4)
on tissue lactate and malondialdehyde (MDA) levels after spinal cord trauma (SCT)
in rabbits were studied. Subjects. Thirty New Zeland rabbits. Interventions. The
rabbits were divided equally into three groups: group I was the sham- operated
group, group II suffered from SCT but received no treatment, group III was given a
dose of 100 mg/kg of magnesium sulfate intravenously at 5th minute after SCT.
Measurements. The lactate and MDA levels were measured in contused spinal cord
tissue at 60 minutes after SCT. There was a significant increase of lactate and MDA
levels in group II (p < 0.05) when compared with groups I and III, and a significant
increase in the level of MDA in group III compared with group I, and also a
significant decrease compared with group II, which was the trauma group without
treatment (p < 0.05). Conclusion. The findings of this study showed that magnesium
sulfate can attenuate the increase of tissue MDA and supply a normalization of
lactate levels following SCT which may be related to the neuroprotective effects of
(MgSO4).
Keywords: lactate, lipid peroxidation, magnesium sulfate, malondialdehyde, spinal
cord trauma
Methods
Acute spinal cord trauma is a destructive injury and
has two pathophysiological components: primary
and secondary injury [1, 2]. Primary injury is the
initial mechanical loss to the spinal cord that results
in disruption of neural and vascular structures but
secondary injury is a progressive cell injury that
damages intact, adjacent tissue [1, 2].
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During neuronal injury, ATP depletion causes an
increase in anaerobic metabolism that leads to lactate accumulation. Excitatory amino acids (EAAs:
mainly glutamate and aspartate) are released in
excessive amounts from terminals of ischemic or
traumatically injured neurons, leading to N-methylD_aspartate (NMDA) receptor activation [3-5]. Ion
pump failure, due to ATP depletion and NMDA receptor activation, causes an intracellular increase of
Ca2+ concentration. Ca2+ overload also inhibits
EFFECTS OF MAGNESIUM SULFATE ON SPINAL CORD TISSUE LACTATE
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Table 1. The heart rate (HR), mean arterial pressure (MAP), arterial oxygen (PaO2), carbondioxide (PaCO2)
values of all groups (means ± SD).
Study group
Group I
Before laminectomy
60 minutes after laminectomy
Group II
Before spinal cord trauma
60 minutes after spinal cord trauma
Group III
Before spinal cord trauma
60 minutes after spinal cord trauma
HR
MAP
PaO2
PaCO2
244 ± 6.6
247 ± 7.7
74 ± 2.7
75 ± 2.5
96.39 ± 2.1
97.33 ± 1.8
28.40 ± 1.6
27.45 ± 1.9
242 ± 8.7
268 ± 8.1*
73 ± 2.9
68 ± 2.3*
97.12 ± 2.3
95.16 ± 2.5
26.35 ± 1.7
27.32 ± 2.1
243 ± 9.1
257 ± 8.3*
72 ± 2.7
67 ± 2.6*
98.22 ± 1.7
97.66 ± 2.2
29.15 ± 1.5
28.15 ± 1.7
* Compared group to I, p < 0.05.
pyruvate dehydrogenase. Suppression of the pyruvate dehydrogenase activity inhibits the decarboxylation of pyruvate to acetyl coenzyme-A and consequently causes anaerobic glycolysis, glycogenolysis
and lactate accumulation. This accumulation leads
to retardation of the extrusion of Ca2+ [6]. Increased
Ca2+ triggers Ca dependent lytic enzymes such as
xanthine oxidase, phospholipase and ornitin decarboxylase [7, 8]. These enzymes cause elevation of
oxygen free radicals lipolysis and proteolysis. Activation of phospholipase-C induces the release of free
fatty acids that leads to the depletion of membrane
phospholipids. This results in altered permeability
and further Ca2+ influx [9]. Lactate accumulation
causes an intracellular Ca2+ increase that leads to
further ATP depletion and Ca2+ influx which results
in further lactate accumulation and MDA formation.
Secondary injury may be prevented by pharmacological agents. Magnesium sulfate (MgSO4) is an
effective tissue protective agent due to potent blockage of N methyl-D-aspartate (NMDA) receptor activation, and consequently free radical formation, lipid
peroxidation and lactate accumulation [10-14]. When
tissue concentration of lactate exceeded 20-25
lg/gww (gram wet weight) the destructive effect
became perceptible [15, 16]. Eventually, both tissue
lactate and MDA may be considerable features associated with progressively worsening cellular effects.
Statistical analysis
All values are expressed as means ± SD. One way
analysis variance and Tukey’s honest significant difference (post hoc) tests were used for the evaluation
of lactate and MDA results.
Two-way analysis of variance for repeated measures and paired t test were used for evaluating arte-
rial blood gas and hemodynamic results between
groups.
Results
The mean arterial pressure, blood gases and heart
rates were similar in all groups before SCT. There
were significant differences in MAP and HR values
between group I and the other groups 60 minutes
after SCT (p < 0.05) (table 1).
The levels of group I were considered the baseline
levels for MDA and lactate. There was a significant
increase in group II (p < 0.05) in lactate and MDA
levels when compared with groups I and III (table 2).
There was no significant elevation of the lactate level
in group III, compared with group I.
Discussion
In our study, in the sham operated group (group I)
and in group III (Mg SO4 treated group), the lactate
concentrations were below toxic levels, and the
MDA levels were also low, showing a good correlaTable 2. Spinal cord tissue lactate and malondialdehyd (MDA) levels (mean ± SD) of each group.
Lactate
(lmol/gwwwet
weight)
MDA
(nmol/gwwwet
weight)
Group I
Group II
Group III
15.70 ± 2.40 27.87 ± 2.82 17.93 ± 2.79
74.66 ± 11.08 136.04 ± 9.86 92.51 ± 10.42
Group I: sham operated group. Group II: spinal cord trauma
delivered and non- treated group. Group III: spinal cord
trauma delivered and MgS04 treated group.
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M. ÖZDEMIR, ET AL.
tion with the lactate concentrations, as mentioned in
the introduction. So our results demonstrated that
Mg SO4 treatment inhibited the increase in tissue
lactate and MDA levels. The increases of HR and
decrease of MAP values were significant in group II.
This may be the detrimental effect of spinal cord
trauma.
The tissue lactate and MDA levels reached a high
value during the first few minutes of traumatic or
ischemic brain injury, it continued to accumulate and
the maximum lactate and MDA levels were reached 1
hour after brain injury [17, 18]. Therefore we measured spinal tissue lactate and MDA levels 1 hour
after SCT.
Mg2+ plays a pivotal role in the metabolism of
carbohydrates, fats, and proteins including glycolysis, oxidative phosphorylation, and protein synthesis
[19]. Mg 2+ also plays a vital role in regulating ribosomal RNA and DNA structure. From this brief summary, it can be seen that Mg 2+ has actions opposite
to those of Ca2+ in maintaining membrane integrity
and storage utilization of energy [20, 21]. Mg2+ is
essential for NA+ –K + –ATPase function, and it suppresses the decline in cerebral ischemia and spinal
trauma [15, 22, 23]. It was emphasized that NMDA
receptor operated channels play a major role in
excess Ca2+ influx and the release of Ca2+ from intracellular stores [4, 5, 21]. Mg 2+ blocks the NMDA
receptor ion channel complex in the brain and in the
spinal cord [24, 25]. In addition, recent studies have
demonstrated that EAA A1 receptors are modulated
by local Mg 2+ concentrations and that high concentrations of Mg 2+ may inhibit the presynaptic EAA
release [26, 27]. Treatment with MgSO4 may function
to limit excitotoxin-induced secondary neuronal
damage [27, 28]. In previous studies [29, 30] it has
been stated that excess Mg 2+ markedly inhibited
lactate production and high energy phosphate breakdown during anoxia. Mg 2+ activates pyruvate carboxylase and other kinase enzymes in gluconeogenesis and enhances the glucose production while
inhibiting lactate production and concomitantly lipid
peroxidation [31]. Mg 2+ activates the synthesis of
membrane integrity [21, 31].
We used 100 mg/kg MgSO4 as a dose of 100 mg/kg
intravenously. Although different dose schedules
exists, a dose of 100 mg/kg can be used in further
clinical studies, but higher doses may be harmful
[32].
In vivo pretreatment with Mg2+ attenuated its
decline in brain tissue, significantly improved neurological outcome [33] and protected against irreversible damage after spinal ischemia [34], whereas preinjury dietary depletion of Mg2+ resulted in lower
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Mg2+ concentration in the brain and worsened the
neurological outcome [35]. Post ischemic and post
injury intravenous Mg2+ treatment improved histological changes and the neurological outcome in several studies [36, 37]. Mg2+ treatment also attenuated
the increase of lactate and MDA levels in other studies [13, 35] and also attenuated [38-40] the decrease
of endogen antioxidant activity in brain tissue after
traumatic head injury in rabbits [41].
We conclude that MgSO4 is an important agent in
the normalization of lactate levels and in suppressing
the increase in MDA levels in traumatic spinal cord
tissue. However, further studies should be performed in the clinical use of MgSO4 and its protective
effects at a cellular level.
References
1. Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ,
Boulos PT, Ellegala DB, Dumont AS. Acute spinal cord
injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 2001; 24: 254-64.
2. Sekhon LH, Fehlings MG. Epidemiology, demographics,
and pathophysiology of acute spinal cord injury. Spine
2001; 26 (Suppl): S2-S12.
3. Allen AR. Surgery of experimental lesions of the spinal
cord equivalent to crush injury of fracture dislocation of
the spinal column. J Amer med Ass 57: 878-80.
4. Feldman Z, Gurevitch B, Artru AA, Oppenheim A,
Shohami E, Reichenthal E, Shapira Y. Effect of magnesium given 1 hour after head trauma on brain edema and
neurological outcome. J Neurosurg 1996; 85: 131-7.
5. Greensmith L, Mooney EC, Waters HJ, HoulihanBurne DG, Lowrie MB. Magnesium ions reduce motor
neuron death following nerve injury or exposure to
N-methyl-D-aspartate in the developing rat. Neuroscience 1995; 68: 807-12.
6. Katayama Y, Fukuchi T, Mc Kee A, Terashi A. Effect of
hyperglycemia on pyruvate dehydrogenase activity and
energy metabolites during ischemia and reperfusion in
gerbil brain. Brain Res 1998; 788: 302-4.
7. Peters T. Calcium in physiological and pathological cell
function. Eur Neurol 1986; 25: 27-44.
8. Shapira Y, Yadid G, Cotev S, Shohami E. Accumulation of
calcium in the brain following head trauma. Neurol Res
1989; 11: 169-72.
9. Reilly PM, Schiller HJ, Bulkley GB. Pharmacologic
approach to tissue injury mediated by free radicals and
other reactive oxygen metabolites. Am J Surg 1991; 161:
488-503.
10. Heath DL, Vink R. Optimization of magnesium therapy
after severe diffuse axonal brain injury in rats. J Pharmacol Exp Ther 1999; 288: 1311-6.
EFFECTS OF MAGNESIUM SULFATE ON SPINAL CORD TISSUE LACTATE
11. Lang-Lazdunski L, Heurteaux C, Dupont H, Widmann C,
Lazdunski M. Prevention of ischemic spinal cord injury:
comparative effects of magnesium sulfate and riluzole.
J Vasc Surg 2000; 32: 179-89.
12. Simpson JI, Eide TR, Schiff GA, Clagnaz JF, Hossain I,
Tverskoy A, Koski G. Intrathecal magnesium sulfate
protects the spinal cord from ischemic injury during
thoracic aortic cross-clamping. Anesthesiology 1994; 81:
1493-9; (discussion 26A-27A).
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 18/06/2017.
13. Üstün ME, Gurbilek M, Ak A, Vatansev H, Duman A.
Effects of magnesium sulfate on tissue lactate and malondialdehyde levels in experimental head trauma.
Intensive Care Med 2001; 27: 264.
14. Kelleher JA, Chan PH, Chan TY, Gregory GA. Modification of hypoxia-induced injury in cultured rat astrocytes
by high levels of glucose. Stroke 1993; 24: 855-63.
15. Levin RM, Haugaard N, Hess ME. Opposing actions of
calcium and magnesium ions on the metabolic effects of
epinephrine in rat heart. Biochem Pharmacol 1976; 25:
1963-9.
16. Rolfsen ML, Davis WR. Cerebral function and preservation during cardiac arrest. Crit Care Med 1989; 17: 28392.
17. Ildan F, Polat S, Oner A, Isbir T, Gocer AI, Tap O,
Kaya M, Karadayi A. Effects of naloxone on sodium- and
potassium-activated
and
magnesium-dependent
adenosine-5’-triphosphatase activity and lipid peroxidation and early ultrastructural findings after experimental spinal cord injury. Neurosurgery 1995; 36: 797-805.
18. Barut S, Canbolat A, Bilge T, Aydin Y, Cokneseli B,
Kaya U. Lipid peroxidation in experimental spinal cord
injury: time-level relationship. Neurosurg Rev 1993; 16:
53-9.
19. Ebel H, Gunter T. Magnesium metabolism. J Clin Chem
Clin Biochem 1980; 18: 257.
20. Rolfsen ML, Davis WR. Cerebral function and preservation during cardiac arrest. Crit Care Med 1989; 17: 28392.
21. Simpson JI, Eide TR, Schiff GA, Clagnaz JF, Hossain I,
Tverskoy A, Koski G. Intrathecal magnesium sulfate
protects the spinal cord from ischemic injury during
thoracic aortic cross-clamping. Anesthesiology 1994; 81:
1493-9; (discussion 26A-27A).
22. Ustun ME, Bariskaner H, Yosunkaya A, Gurbilek M,
Dogan N. Effects of magnesium sulfate on Na+,K+ATPase and intracranial pressure level after cerebral
ischemia. Magnes Res 2004; 17: 169-75.
channels in mouse central neurones. Nature 1984; 307:
462-5.
26. Pagg G. L-Glutamate excitatory amino acid receptors
and brain function. Trend neurosci 1985; 76: 207-10.
27. Rothman S. Synaptic release of excitatory amino acid
neurotransmitter mediates anoxic neuronal death. J
Neurosci 1984; 4: 1884-91.
28. Choi DW. Ionic dependence of glutamate neurotoxicity.
J Neurosci 1987; 7: 369-79.
29. Ildan F, Polat S, Oner A, Isbir T, Gocer AI, Tap O,
Kaya M, Karadayi A. Effects of naloxone on sodium- and
potassium-activated
and
magnesium-dependent
adenosine-5’-triphosphatase activity and lipid peroxidation and early ultrastructural findings after experimental spinal cord injury. Neurosurgery 1995; 36: 797-805.
30. Zager EL, Ames 3rd A. Reduction of cellular energy
requirements. Screening for agents that may protect
against CNS ischemia. J Neurosurg 1988; 69: 568-79.
31. Lehninger AL. The critic acid cycle. In: Lehninger AL,
ed. The biosynthesis of lipids, Principles of biochemistry. New York: Worth, 1987; (435-66 and 538-614).
32. Kaptanoglu E, Beskonakli E, Okutan O, Selcuk
Surucu H, Taskin Y. Effect of magnesium sulphate in
experimental spinal cord injury: evaluation with ultrastructural findings and early clinical results. J Clin Neurosci 2003; 10: 329-34.
33. McIntosh TK, Faden AI, Yamakami I, Vink R. Magnesium deficiency exacerbates and pretreatment
improves outcome following traumatic brain injury in
rats: 31P magnetic resonance spectroscopy and behavioral studies. J Neurotrauma 1988; 5: 17-31.
34. Vacanti FX, Ames 3rd A. Mild hypothermia and Mg++
protect against irreversible damage during CNS
ischemia. Stroke 1984; 15: 695-8.
35. Kaplan S, Ulus AT, Tutun U, Aksoyek A, Ozgencil E,
Saritas Z, Apaydin N, Pamuk K, Can Z, Surucu S,
Katircioglu SF. Effect of Mg2SO4 usage on spinal cord
ischemia-reperfusion injury: electron microscopic and
functional evaluation. Eur Surg Res 2004; 36: 20-5.
36. Lang-Lazdunski L, Heurteaux C, Dupont H, Widmann C,
Lazdunski M. Prevention of ischemic spinal cord injury:
comparative effects of magnesium sulfate and riluzole.
J Vasc Surg 2000; 32: 179-89.
37. McIntosh TK, Vink R, Yamakami I, Faden AI. Magnesium protects against neurological deficit after brain
injury. Brain Res 1989; 482: 252-60.
23. Groenendaal F, Shadid M, McGowan JE, Mishra OP, van
Bel F. Effects of deferoxamine, a chelator of free iron,
on NA(+), K(+)-ATPase activity of cortical brain cell
membrane during early reperfusion after hypoxiaischemia in newborn lambs. Pediatr Res 2000: 48.
38. Lin JY, Chung SY, Lin MC, Cheng FC. Effects of magnesium sulfate on energy metabolites and glutamate in the
cortex during focal cerebral ischemia and reperfusion in
the gerbil monitored by a dual-probe microdialysis technique. Life Sci 2002; 71: 803-11.
24. Mayer ML, Westbrook GL, Guthrie PB. Voltagedependent block by Mg2+ of NMDA responses in spinal
cord neurones. Nature 1984; 309: 261-3.
39. Van den Bergh WM, Zuur JK, Kamerling NA, van
Asseldonk JT, Rinkel GJ, Tulleken CA, Nicolay K. Role
of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid
hemorrhage. J Neurosurg 2002; 97: 416-22.
25. Nowak L,
Bregestovski P,
Ascher P,
Herbet A,
Prochiantz A. Magnesium gates lutamate-activated
173
M. ÖZDEMIR, ET AL.
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 18/06/2017.
40. Westermaier T,
Hungerhuber E,
Zausinger S,
Baethmann A, Schmid-Elsaesser R. Neuroprotective
efficacy of intra-arterial and intravenous magnesium
sulfate in a rat model of transient focal cerebral
ischemia. Acta Neurochir 2003; 145: 393-9; (discussion
399).
174
41. Ustun ME, Duman A, Ogun CO, Vatansev H, Ak A.
Effects of nimodipine and magnesium sulfate on endogenous antioxidant levels in brain tissue after experimental head trauma. J Neurosurg Anesthesiol 2001; 13: 22732.