We examined the role of hippocampal galanin in an animal model of status epilepticus (SE). Control rats showed abundant galanin-immunoreactive (Gal-IR) fibers in the dentate hilus, whereas no Gal-IR neurons were observed. Three hours after the onset of self-sustaining SE (SSSE), induced either by intermittent stimulation of the perforant path for 30 min (PPS) or by injection of lithium and pilocarpine, Gal-IR fibers disappeared in the hilus and remained absent for up to 1 week afterward. Twelve hours after the induction of SE by PPS or 3 hr after pilocarpine administration, Gal-IR neurons appeared in the hilus; these neurons increased in number after 1 d and gradually declined 3 and 7 d later. Galanin concentration in the hippocampus, measured by ELISA, significantly decreased on the plateau of SSSE and increased 24 hr after PPS. Galanin (0.05 nmol) injected into the hilus prevented the induction of SSSE, and 0.5 nmol of galanin stopped established SSSE. These effects were attenuated by galanin receptor antagonists (M35 > M40 >/= M15). 2-Ala-galanin (5 nmol), a putative agonist of galanin type 2 receptors, prevented but was unable to stop SSSE. M35 facilitated the development of SSSE when given before PPS. We suggest that hippocampal galanin acts as an endogenous anticonvulsant via galanin receptors. SE-induced galanin depletion in the hippocampus may contribute to the maintenance of seizure activity, whereas the increase of galanin concentration and the appearance of galanin-immunoreactive neurons may favor the cessation of SSSE. The seizure-protecting action of galanin SSSE opens new perspectives in the treatment of SE.

Substance P (SP), a member of the tachykinin family, is widely distributed in the central nervous system and is involved in a variety of physiological processes including cardiovascular function, inflammatory responses, and nociception. We show here that intrahippocampal administration of SP triggers self-sustaining status epilepticus (SSSE) in response to stimulation of the perforant path for periods too brief to have any effect in control rats, and this SSSE generates a pattern of acute hippocampal damage resembling that known to occur in human epilepsy. The SP receptor (SPR) antagonists, spantide II and RP-67,580, block both the initiation of SSSE and SSSE-induced hippocampal damage and terminate established anticonvulsantresistant SSSE. SSSE results in a rapid and dramatic increase in the expression of preprotachykinin A (a precursor of SP) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus as well as in hippocampal mossy fibers. SP also increases glutamate release from hippocampal slices. Enhanced expression of SP during SSSE may modulate hippocampal excitability and contribute to the maintenance of SSSE. Thus, SPR antagonists may constitute a novel category of drugs in antiepileptic therapy.Feed-forward excitation travels along a hippocampal trisynaptic circuit, in which dentate gyrus (DG) granule cells make excitatory synaptic connections via mossy fibers onto CA3 pyramidal neurons that, in turn, form excitatory synaptic connections onto CA1 pyramidal neurons (1, 2). This hippocampal circuit displays considerable neurochemical plasticity in response to lesions and change in afferent activity (3-6). Substance P (SP), a member of peptides belonging to the tachykinin family, is present in low concentration in the rat hippocampus (7,8). However, its expression, like that of other neuropeptides, shows considerable plasticity and can be regulated by drugs (9-11), neuronal activity (12, 13), and convulsant kainic acid (14,15). SP is well established as a neurotransmitter͞neuromodulator (16) and is released by various stimuli (17, 18). There is evidence to suggest that SP modulates neuronal membrane excitability by virtue of slow synaptic currents (19), raises intracellular Ca 2ϩ concentrations (20), and enhances responses to excitatory amino acids (21). Using a new animal model (22), we now present evidence that SP plays an important role in the severe seizures seen in selfsustaining status epilepticus (SSSE) and in modulating hippocampal excitability. MATERIALS AND METHODS Induction and Analysis of Status Epilepticus (SE).Male Wistar rats (240-280 g) were implanted under anesthesia (ketamine 60 mg kg Ϫ1 ͞xylazine 15 mg kg Ϫ1) with a bipolar stimulating electrode into the angular bundle of the perforant path and a bipolar recording electrode into the granule cell layer of the ipsilateral DG. To standardize the position of the electrode, only animals in which population spike amplitude was Ն2 mV were used. Seven days after surgery, animals were stimulated in the awake state for 30 min wit...

Summary:Purpose: Several experimental paradigms of seizure induction that produce epilepsy as a consequence have been shown to be associated with the proliferation of dentate granule cells. In developing animals, the acute sequela of hilar damage and the chronic sequelae of spontaneous seizures and mossy fiber synaptic reorganization, in response to status epilepticus, occur in an age-dependent manner. We investigated seizure-induced granule cell neurogenesis in developing rat pups to study the association between hilar injury, granule cell neurogenesis, and epilepsy.Methods: Rat pups of 2 and 3 weeks postnatal age were subjected to lithium-pilocarpine status epilepticus (LiPC SE). Rats were given bromodeoxyuridine (BrdU; 50 mglkg intraperitoneal) twice daily for 4 days beginning 3 days after SE to label dividing cells. Routine immunocytochemistry and quantification of BrdU labeling by image analysis were performed. Results were compared with previously reported data on cellular injury, mossy fiber sprouting, and spontaneous seizures in rat pups of these ages after LiPC SE.

Although epilepsy often begins in childhood, factors that contribute to the development of epilepsy as a consequence of status epilepticus (SE) during early development are poorly understood. We investigated animal models in which seizure‐induced epileptogenicity could be studied. Rats undergoing self‐sustaining SE induced by perforant path stimulation (PPS) at the ages of postnatal day 21 (P21) and P35 were compared with those subjected to SE by lithium and pilocarpine (LiPC). Although only one animal subjected to PPS at P21 developed chronic spontaneous seizures by several months of observation, all the animals subjected to PPS at P35 became epileptic. In the LiPC model, however, most of the rat pups subjected to SE at P21 became epileptic. Animals with spontaneous seizures showed increased inhibition in the dentate gyrus, a characteristic of the epileptic brain, with evidence of mossy fiber synaptic reorganization. Examination of circuit recruitment by c‐Jun immunohistochemistry showed activation restricted to the hippocampus in P21 animals subjected to PPS, although extensive activation of hippocampal and extrahippocampal structures was seen in pups subjected to PPS‐induced self‐sustaining SE at P35 or LiPC SE at P21. These results demonstrate that the appearance of epilepsy as a consequence of SE is influenced by the type of insult as well as by age‐dependent circuit recruitment. Ann Neurol 2000;48:580–589