However protection against kainic acid
However, protection against kainic acid-induced injury was not found by Lin et al. (2003) in the rats with AAV-GAL vector-mediated galanin overexpression, even though these animals, as mentioned earlier, exhibited attenuated of seizure severity. Although the reason for the controversy between the studies of Haberman et al. (2003) and Lin et al. (2003) is not clear, it shows that under the same experimental conditions, anticonvulsant and neuroprotective affects of galanin may occur independently.
Further support for neuroprotective properties of galanin comes from the studies in which excitotoxic injury was induced by an insult other than seizures. Zini et al. (1993a) showed that galanin inhibited the release of glutamate from rat hippocampal slices under conditions of hypoxia induced by oxygen deprivation. Neuroprotective effects were observed for both native galanin and for GalR2-preferring galanin (1–16). Elliott-Hunt et al. (2004) reported that both organotypic and primary hippocampal cell cultures from early postnatal galanin knockout mice were more vulnerable to both glutamate- and staurosporine-induced cell death, than cell cultures from wild type littermates. Conversely, organotypic cultures obtained from galanin-overexpressing mice exhibited enhanced resistance to staurosporine-induced neurotoxicity. Exogenous activation of GalR1/GalR2 with galanin (1–29), or GalR2 with galanin (2–11) were equally effective in protecting wild type organotypic cultures from neurotoxic action of staurosporine. These data suggest that galanin acting through GalR2 protects Protease Inhibitor Library not only from excitotoxic effects of glutamate (a primary cause of neuronal injury in seizures), but also from neuronal death unrelated to seizures (staurosporine-induced apoptosis). Furthermore, enhanced sensitivity of galanin knockout hippocampal cell cultures to glutamate suggests that galanin antagonizes glutamatergic transmission on postsynaptic level, probably through GalR2 subtype (although the authors did not test GalR2 agonists in glutamate model of excitotoxicity). We used a model of hypoxic neuronal necrosis induced by NaCN (Niquet et al., 2003) to study neuroprotective properties of GalR subtypes. Both primary cortical cell cultures from prenatal day 17 and primary dentate gyrus cell cultures from postnatal day 3 rat pups expressed both GalR1 and GalR2. Activation of GalR1/GalR2 by galanin (1–29) and preferential activation of GalR2 by galanin (2–11) or D-Trp-2-Galanin (1–29) were equally effective in protecting cell cultures from chemical hypoxia, as was quantified by measuring lactate dehydrogenase release. Furthermore, pretreatment of the cell cultures with GalR2 PNA significantly attenuated neuroprotective effects of GalR1/GalR2 activation by galanin (1–29) (Niquet et al., 2004).
Galanin and neuronal plasticity Seizures are accompanied not only by neurodegenerative, but also by neuronal plastic changes, which are purposed to restore lost neuronal connections or to compensate for neuronal injury. An example for the latter is neuronal progenitor proliferation, which is induced by seizures in the dentate gyrus (Parent et al., 1997). Dentate gyrus of rodents contains small number of undifferentiated neuronal progenitors, which proliferate at low rate, and some of them differentiate into neurons (Kuhn et al., 1996). Seizures induce dramatic increase in the rate of neuronal progenitor proliferation and their neuronal differentiation (Parent et al., 1997), a process, which may be reparative by virtue, purposed to compensate for the hilar interneuron loss and to restore of dentate granule cell inhibition, but was suggested to be proconvulsant in fact, as many of neuronal progenitors become excitatory dentate granule ectopically located in the hilus of the dentate gyrus, an area normally containing inhibitory interneurons (Scharfman et al., 2003). We recently found (Mazarati et al., 2004a) that focal downregulation of GalR2 in the dentate gyrus blocked seizure-induced neurogenesis and neuronal differentiation, without affecting basal neurogenesis (Fig. 6). On the other hand, no differences in both basal and seizure-induced neurogenesis were observed between wild type and GalR1 knockout mice (Mazarati et al., 2004b). While physiological significance of seizure-induced neurogenesis in the hippocampus is uncertain, this phenomenon clearly represents an example of neuronal plasticity in response to stress, particularly to excitotoxic insult; our findings implicate galanin acting through GalR2 in regulating this form of neuronal plasticity associated with seizures. With regard to the described results, it is worth mentioning, that the expression of GalR2, and to a much lesser extent GalR1, as well as of galanin peptide transcript have been recently shown in the mouse embryonic stem cells (Tarasov et al., 2002), which implicates galanin in regulating growth and differentiation of mature cell precursors.