Prolonged attenuation of amygdala-kindled seizure measures in rats by convection-enhanced delivery of the N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA.
Convection-enhanced delivery (CED) permits the homogeneous distribution of therapeutic agents throughout localized regions of the brain parenchyma without causing tissue damage as occurs with bolus injection. Here, we examined whether CED infusion of the N-type calcium channel antagonists omega-conotoxin GVIA (omega-CTX-G) and omega-conotoxin MVIIA (omega-CTX-M) can attenuate kindling measures in fully amygdala-kindled rats. Rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received infusions of vehicle, omega-CTX-G (0.005, 0.05, and 0.5 nmol), omega-CTX-M (0.05, 0.15, and 0.5 nmol), proteolytically inactivated omega-CTX-M (0.5 nmol), or carbamazepine (500 nmol) into the stimulation site. CED of omega-CTX-G and omega-CTX-M over a 20-min period resulted in a dose-dependent increase in the afterdischarge threshold and a decrease in the afterdischarge duration and behavioral seizure score and duration during a period of 20 min to 1 week after the infusion, indicating an inhibitory effect on the triggering and expression of kindled seizures. The protective effects of omega-conotoxins reached a maximum at 48 h postinfusion, and then they gradually resolved over the next 5 days. In contrast, carbamazepine was active at 20 min but not at 24 h after the infusion, whereas CED of vehicle or inactivated omega-CTX-M had no effect. Except for transient tremor in some rats receiving the highest toxin doses, no adverse effects were observed. These results indicate that local CED of high-molecular-weight presynaptic N-type calcium channel blockers can produce long-lasting inhibition of brain excitability and that they may provide prolonged seizure protection in focal seizure disorders.
Gasior
Maciej
M
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
White
Natalie A
NA
Rogawski
Michael A
MA
D000679:Amygdala / Q000187:drug effects*; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D002220:Carbamazepine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D020866:omega-Conotoxin GVIA / Q000008:administration & dosage* / Q000378:metabolism; D020960:omega-Conotoxins / Q000008:administration & dosage* / Q000378:metabolism
D002121:Calcium Channel Blockers; D020960:omega-Conotoxins; D002220:Carbamazepine; C078452:ziconotide; D020866:omega-Conotoxin GVIA
Neurology. 2005 Jun 28;64(12 Suppl 3):S2-11
15994220
Neuropharmacology. 1994 Feb;33(2):255-8
8035912
Brain Res Brain Res Rev. 2004 Mar;44(2-3):141-53
15003390
Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2076-80
8134351
Neuropharmacology. 1984 Oct;23(10):1117-23
6521848
Science. 1985 Dec 20;230(4732):1338-43
4071055
J Mol Biol. 1982 May 5;157(1):105-32
7108955
Int J Pept Protein Res. 1995 Sep-Oct;46(3-4):320-5
8537186
Eur J Pharmacol. 1989 Dec 19;174(2-3):261-6
2560980
J Neurosurg. 2002 Oct;97(4):905-13
12405380
Eur J Pharmacol. 1993 Jul 20;238(2-3):383-6
8104812
Biochemistry. 1987 Apr 21;26(8):2086-90
2441741
Neuron. 1993 Nov;11(5):895-902
7902110
Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
4110397
Epilepsia. 2003 Nov;44(11):1425-33
14636351
J Neurosci. 1994 Sep;14(9):5613-22
8083757
Peptides. 2000 Apr;21(4):491-501
10822104
Pain. 1995 Jan;60(1):83-90
7715945
Pflugers Arch. 1995 Apr;429(6):873-5
7603842
Psychopharmacology (Berl). 1996 Jul;126(1):85-90
8853221
J Mol Recognit. 2000 Mar-Apr;13(2):55-70
10822250
J Neurosurg. 1995 Jun;82(6):1021-9
7539062
J Biol Chem. 2003 May 30;278(22):20171-8
12654924
Annu Rev Pharmacol Toxicol. 1995;35:707-34
7598513
Neurosci Lett. 1988 Aug 15;91(1):84-8
2845309
Neurosurgery. 2003 Feb;52(2):388-93; discussion 393-4
12535369
Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):269-79
4110396
Curr Opin Oncol. 2000 May;12(3):187-93
10841189
Br J Pharmacol. 1991 Jul;103(3):1733-9
1657265
Epilepsy Res. 1999 Feb;33(2-3):159-67
10094427
Eur J Neurosci. 1991;3(10):992-1000
12106257
Brain Res Bull. 1981 Dec;7(6):629-33
7326579
Trends Neurosci. 1997 May;20(5):204-12
9141196
J Neurosurg. 1999 Feb;90(2):315-20
9950503
J Neurosurg. 1999 Feb;90(2):321-31
9950504
J Biol Chem. 1986 May 15;261(14):6230-3
2939072
Epilepsia. 1976 Jun;17(2):197-206
947748
Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5058-62
1317580
Biochemistry. 1995 Jun 27;34(25):8076-81
7794920