Epilepsy

The discovery of galanin's effects on epilepsy, where it acts as an anticonvulsant, is a good example of the pre-synaptic inhibitory effects of galanin on glutamate but not on GABA release (Ben-Ari 1990), and shows how it acts as a postsynaptic hyperpolarizing substance to reduce run-away discharges alike (Mazarati et al. 1992, 1998, 2000, 2001). The galanin agonist, galnon, suppresses phenyltetrazole-induced (40 mg/kg) seizures when injected i.p. (2 mg/kg) (Saar, 2002).

Additional information on the pharmacological potential of galanin receptor ligands is now forthcoming from transgenic studies on the role of galanin (Table 16.6). The galanin-deficient mice generated by Wynick et al. (1998) has lowered seizure threshold, and some impairment of the development of sensory neurones. Mice strains that overexpress galanin under the DßH promoter in noradrenergic cells (Steiner et al. 2001), or under the PDGF ß-chain promoter in most forebrain neurones (Blakeman et al. 2001), have elevated seizure thresholds, owing to the hyperpolarizing effects of galanin in the hippocampus at both CA1/CA3 and the dentate gyrus area (Kokaia et al. 2001).

The most instructive for the role of galanin receptors are the GalR1(-/—) mice generated by Iisma et al. which have been studied in several contexts (Iismaa, unpublished material). The most striking phenotype so far found (see above) is the occurrence of spontaneous seizures in some founders, strongly suggesting that GalR1 agonists will be potent anticonvulsant drugs. GalR1(—/—) transgenic mice have been generated by truncated disruption of the GalR1 gene and these animals are being characterized in several laboratories including our own. In some founders spontaneous seizures were observed (Iismaa, Bartfai, unpublished observations). These data are in congruence with the preliminary data from Mazarati, Wasterlain and Langel, who used antisense oligonucleotides to the GalR1 to knock down the expression of GalR1 in vivo, and then found increased seizure susceptibility when GalR1 function was impaired (Mazarati et al. 2001).

Table 16.6 Galanin transgenic mice strains suggest that galanin controls hippocampal excitability in seizure models via the galanin type 1 receptor (Ga1R1)

Strain

Expression pattern

Major phenotype

Galanin (—/ — )1

Galanin deficient

Sensory neurones | enhanced hippocampal excitability

GALOE—DßH2

3-5 fold overexpression in NE neurones

Suppressed hippocampal excitability

Cognitive deficit

GALOE—PDGFß3

5-20 fold overexpression in all CNS and most peripheral neurones

Suppressed hippocampal excitability

Altered parasympathetic tone

Ga1R1 (—/—)4

Ga1R1 deficient

Enhanced hippocampal excitability

Spontaneous seizures in some founder lines

1 Holmes et al. 2000.

2Steiner etal. 2001 (Galanin gene proceeded by the dopamine beta hydroxylase promoter). 3Holmgren, Kahl et al. 2000 (Galanin gene proceeded by the dopamine beta PDGFb promoter). 4Iismaa etal. 2001.

1 Holmes et al. 2000.

2Steiner etal. 2001 (Galanin gene proceeded by the dopamine beta hydroxylase promoter). 3Holmgren, Kahl et al. 2000 (Galanin gene proceeded by the dopamine beta PDGFb promoter). 4Iismaa etal. 2001.

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