Calcium Antagonism in Neonatal Rats With Kaolin-Induced Hydrocephalus

Abstract

Juvenile rats with kaolin-induced hydrocephalus have reduced brain injury if treated with nimodipine or magnesium sulfate. Experiments were conducted to determine if the neuroprotective effects could be replicated in neonatal rats with experimental hydrocephalus at an age comparable to prematurely born humans. In a blinded and randomized manner, drugs were administered for 14 days beginning 7 days after induction of hydrocephalus. Nimodipine was given twice daily by subcutaneous injections. Daily doses greater than 38 mg/kg of body weight were fatal. Daily doses of 3.8 to 30 mg/kg were not associated with behavioral, structural, or biochemical improvements. Magnesium chloride was administered via daily subcutaneous minipump infusion (0.87 or 1.74 mM/kg) along with twice daily injections of 0.74 or 1.48 mM/kg. Magnesium sulfate was administered by twice daily subcutaneous doses of 1.54 or 7.72 mM/kg. Sedation occurred, but there was no statistically significant protection in regard to behavior, brain structure, or brain composition in any of the magnesium experiments. Developmental alterations in calcium channels of the neonatal rat brain could account for differences from prior experiments in young hydrocephalic rats.

Keywords

axon white matter cerebral ventricle myelin calcium channels nimodipine magnesium

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References

McAllister JP II , Chovan P. Neonatal hydrocephalus: mechanisms and consequences . Neurosurg Clin N Am. 1998;9(1):73-93.

Del Bigio MR.

Calcium-mediated proteolytic damage in white matter of hydrocephalic rats?

J Neuropathol Exp Neurol. 2000; 59(11):946-954.

Del Bigio MR , Massicotte EM Protective effect of nimodipine on behavior and white matter of rats with hydrocephalus. J Neurosurg. 2001;94(5):788-794.

Khan OH , Enno T. , Del Bigio MR. Magnesium sulfate therapy is of mild benefit to young rats with kaolin-induced hydrocephalus. Pediatr Res. 2003;53(6):970-976.

Durlach J. , Bara M. , Theophanides T. A hint on pharmacological and toxicological differences between magnesium chloride and magnesium sulphate, or of scallops and men. Magnes Res. 1996; 9(3):217-219.

Heath DL , Vink R. Neuroprotective effects of MgSO4 and MgCl2 in closed head injury: a comparative phosphorus NMR study. J Neurotrauma . 1998;15(3):183-189.

Khan OH , Enno TL , Del Bigio MR Brain damage in neonatal rats following kaolin induction of hydrocephalus . Exp Neurol. 2006;200(2):311-320.

Del Bigio MR , Crook CR , Buist R. Magnetic resonance imaging and behavioral analysis of immature rats with kaolin-induced hydrocephalus: pre- and postshunting observations. Exp Neurol. 1997;148(1):256-264.

Altman J. , Sudarshan K. Postnatal development of locomotion in the laboratory rat. Animal Behav. 1975;23(4):896-920.

10.

Del Bigio MR , Kanfer JN , Zhang YW Myelination delay in the cerebral white matter of immature rats with kaolin-induced hydrocephalus is reversible. J Neuropathol Exp Neurol. 1997; 56(9):1053-1066.

11.

Fern R. , Ransom BR , Waxman SG Voltage-gated calcium channels in CNS white matter: role in anoxic injury . J Neurophysiol. 1995;74(1):369-377.

12.

Westenbroek RE , Bausch SB , Lin RC , et al. Upregulation of L-type Ca2+ channels in reactive astrocytes after brain injury, hypomyelination, and ischemia. J Neurosci. 1998;18(7):2321-2334.

13.

Scriabine A. , van den Kerckhoff W. Pharmacology of nimodipine: a review. Ann N Y Acad Sci. 1988;522:698-706.

14.

Rinkel GJ , Feigin VL , Algra A. , Vermeulen M. , van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2005;(1):CD000277.

15.

Iseri LT , French JH Magnesium: nature's physiologic calcium blocker. Am Heart J. 1984;108(1):188-193.

16.

Bahar M. , Berman S. , Grinshpon Y. , et al. Intracellular Ca++/Mg++ homeostasis during postnatal growth of experimental rats: multiple time-point study. Growth Dev Aging. 2002;66(2):55-62.

17.

Tanaka O. , Sakagami H. , Kondo H. Localization of mRNAs of voltage-dependent Ca(2+)-channels: four subtypes of α1- and βsubunits in developing and mature rat brain . Brain Res Mol Brain Res. 1995;30(1):1-16.

18.

Vance CL , Begg CM , Lee WL , Haase H. , Copeland TD , McEnery MW Differential expression and association of calcium channel α1B and β subunits during rat brain ontogeny. J Biol Chem. 1998; 273(23):14495-14502.

19.

Schluter G. Toxicological investigations with nimodipine: summary of relevant studies. Arzneimittelforschung. 1986;36(12):1733-1735.

20.

Buwalda B. , Naber R. , Nyakas C. , Luiton PG Nimodipine accelerates the postnatal development of parvalbumin and S-100 beta immunoreactivity in the rat brain. Brain Res Dev Brain Res. 1994;78(2):210-216.

21.

Angrisani M. , Loffreda A. , De Santis D. , et al. Interference of prenatal and postnatal exposure to Ca2+-antagonist agents on rat functional development of vascular system. Teratog Carcinog Mutagen. 1989;9(1):39-49.