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A Reggiani

Publications and source records attributed to A Reggiani.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cycloalkyl indole-2-carboxylates as useful tools for mapping the "north-eastern" region of the glycine binding site associated with the NMDA receptor.

A novel series of indole-2-carboxylate analogues of GV 150526 (1) in which the terminal phenyl ring belonging to the side chain present in the position C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindole-2 -carboxylic acid 6b and 3-[2-(norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-c arboxylic acid 6l were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (Ki = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA binding sites) and high in vivo potency after systemic administration by inhibition of convulsion induced by NMDA in mice.

Amantadine↗
PubMed1999

Glycine-site antagonists and stroke.

The excitatory amino acid, (S)-glutamic acid, plays an important role in controlling many neuronal processes. Its action is mediated by two main groups of receptors: the ionotropic receptors (which include NMDA, AMPA and kainic acid subtypes) and the metabotropic receptors (mGluR(1-8)) mediating G-protein coupled responses. This review focuses on the strychnine insensitive glycine binding site located on the NMDA receptor channel, and on the possible use of selective antagonists for the treatment of stroke. Stroke is a devastating disease caused by a sudden vascular accident. Neurochemically, a massive release of glutamate occurs in neuronal tissue; this overactivates the NMDA receptor, leading to increased intracellular calcium influx, which causes neuronal cell death through necrosis. NMDA receptor activation strongly depends upon the presence of glycine as a co-agonist. Therefore, the administration of a glycine antagonist can block overactivation of NMDA receptors, thus preserving neurones from damage. The glycine antagonists currently identified can be divided into five main categories depending on their chemical structure: indoles, tetrahydroquinolines, benzoazepines, quinoxalinediones and pyrida-zinoquinolines.

Journal Article↗
PubMed1999

Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A.

Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. GV196771A exhibited an elevated affinity for the NMDA glycine binding site in rat cerebral cortex membranes (pKi = 7.56). Moreover, GV196771A competitively and potently antagonized the activation of NMDA receptors produced by glycine in the presence of NMDA in primary cultures of cortical, spinal, and hippocampal neurons (pKB = 7.46, 8. 04, and 7.86, respectively). In isolated baby rat spinal cords, 10 microM GV196771A depressed wind-up, an electrical correlate of central sensitization. The antihyperalgesic properties of GV196771A were studied in a model of chronic constriction injury (CCI) of the rat sciatic nerve and in the mice formalin test. In the CCI model GV196771A (3 mg/kg twice a day p.o.), administered before and then for 10 days after nerve ligature, blocked the development of thermal hyperalgesia. Moreover, GV196771A (1-10 mg/kg p.o.) reversed the hyperalgesia when tested after the establishment of the CCI-induced hyperalgesia. In the formalin test GV196771A (0.1-10 mg/kg p.o.) dose-dependently reduced the duration of the licking time of the late phase. These antihyperalgesic properties were not accompanied by development of tolerance. These observations strengthen the view that NMDA receptors play a key role in the events underlying plastic phenomena, including hyperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to classical opioids.

Analgesics, Non-Narcotic↗
PubMed1999

Effects of cholecystokinin peptides and GV 150013, a selective cholecystokininB receptor antagonist, on electrically evoked endogenous GABA release from rat cortical slices.

The effects of cholecystokinin (CCK) agonists and antagonists on spontaneous and electrically evoked endogenous GABA release from rat cerebral cortex slices were evaluated. Neither the nonselective and CCK(B)-selective receptor agonists CCK-8S (3-1,000 nM) and CCK-4 (3-1,000 nM), respectively, nor the selective CCK(B) and CCK(A) receptor antagonists GV 150013 (3-30 nM) and L-364,718 (10-100 nM), respectively, significantly affected spontaneous GABA release. CCK-8S (1-1,000 nM) and CCK-4 (1-1,000 nM) increased the electrically (5 and 10 Hz)-evoked GABA release. On the contrary, GV 150013 (10 and 30 nM) significantly decreased the electrically evoked GABA release only when the slices were stimulated at the higher 10 Hz frequency. The CCK-8S- and CCK-4-induced increases in electrically evoked GABA release were counteracted by GV 150013, but not by L-364,718. Furthermore, GV 150013 at 3 nM shifted to the right the CCK-4 concentration-response curve, whereas at the higher 10 nM concentration it dramatically flattened the curve. Finally, in cortical slices obtained from rats chronically treated with GV 150013, the concentration-response curve of CCK-4 was shifted to the left and the peak effect of the peptide was significantly higher than that observed in naive animals. These results suggest that CCK increases electrically evoked, but not spontaneous, endogenous GABA release from rat cortical slices, possibly by activating local CCK(B) receptors. In addition, chronic treatment with the novel CCK(B) receptor antagonist GV 150013 leads to an enhanced responsiveness of cortical slices to CCK-4 application.

Adamantane↗
PubMed1998

(E)-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid derivatives. A novel class of glycine site antagonists.

The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)-vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi = 7.95 +/- 0.01) and the 4-bromo-5-methyl 6j (pKi = 7.24 +/- 0.01) and 4,5-dimethyl 6g (pKi = 6.70 +/- 0.03) analogues were the most active compounds of the series. Qualitative structure-activity analysis points to a negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced by halo-substituents. QSAR analysis by the Hansch descriptors F, R, pi, and MR, on a subset of compounds with pKi > or = 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions. 6g was found to be a full antagonist (alpha = 0; enhancement of the [3H]TCP binding). The in vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions in mice by both the i.v. and po routes; 6w was the most active compound (ED50 = 3 x 10(-3) (0.8-10) g/kg, i.v. and 30 x 10(-3) (4.5-61) g/kg, p.o.). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.

Acrylamides↗
PubMed1998

Protective effect of GV150526A on the glutamate-induced changes in basal and electrically-stimulated cytosolic Ca++ in primary cultured cerebral cortical cells.

Glutamate-induced changes in intracellular free Ca++ concentration ([Ca++]i) were recorded in resting and electrically-stimulated primary cultures of rat cerebral cortical cells, employing the Ca++ indicator Fura 2. A brief (10 min) exposure to glutamate led to a concentration-dependent basal [Ca++]i increase, measured 30 min after glutamate removal. In order to unmask more subtle modifications in [Ca++]i movements associated with neurosecretion, the glutamate effect was also studied in electrically-stimulated cells. The application of trains (10 s) of electrical pulses (intensity 30 mA, duration 1 ms) induced frequency-related Na+- and Ca++-dependent [Ca++]i transients. A 5 min treatment with 50 microM glutamate reduced to 48% the electrically-evoked [Ca++]i transients, evaluated 30 min after glutamate challenge. The neuroprotective effect of sodium 4,6-dichloro-3-[(E)-3-(N-phenyl)propenamide]indole-2-carboxylate (GV150526A), a new indole derivative with high affinity and selectivity for the glycine site of the NMDA receptor-channel complex, was compared with that of DL-2-amino-5-phosphonopentanoic acid (AP5), ifenprodil, 7-chlorokynurenic acid and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX) on glutamate-induced [Ca++]i changes in resting and electrically-stimulated cells. In both experimental conditions, GV150526A showed to be the most potent compound. Moreover, GV150526A and 7-chlorokynurenic acid were 2-3 times more active in stimulated neurons than in resting neurons, indicating a major involvement of the glycine site in the protection of the cells kept in an active state.

Animals↗
PubMed1997

GV 150526A, 7-Cl-kynurenic acid and HA 966 antagonize the glycine enhancement of N-methyl-D-aspartate-induced [3H]noradrenaline and [3H]dopamine release.

The effect of selective antagonists (7-Cl-kynurenic acid, 3-amino-1-hydroxypyrrolid-2-one (HA 966) and GV 150526A) at strychnine-insensitive glycine sites was studied by measuring how much glycine potentiated the [3H]dopamine and [3H]noradrenaline release induced by 100 microM N-methyl-D-aspartate (NMDA) from superfused striatal and hippocampal synaptosomes, respectively, in a Mg2+-free buffer. Glycine, which per se had no effect on [3H]catecholamine release, concentration-dependently potentiated the effect of NMDA, with similar potency in the two brain regions (EC50 0.25 and 0.27 microM for [3H]dopamine and [3H]noradrenaline release, respectively). 7-Cl-Kynurenic acid reduced the effect of NMDA alone and antagonized the effect of 1 microM glycine, with Ki values of 1.1 and 0.6 microM for [3H]dopamine and [3H]noradrenaline release, respectively. HA 966 did not inhibit the effect of NMDA alone, but reduced the effect of glycine with Ki = 11.5 and 66 microM for [3H]dopamine and [3H]noradrenaline release. GV 150526A inhibited the effect of NMDA alone and potently antagonized the effect of glycine, with Ki = 12.4 and 17.3 nM for [3H]dopamine and [3H]noradrenaline release. Our results are consistent with the possibility that HA 966 is a partial agonist, while 7-Cl-kynurenic acid and GV 150526A are competitive antagonists at the strychnine-insensitive glycine sites. In addition HA 966 shows regional differences in its interaction with the strychnine-insensitive glycine receptor, being about six times more potent on striatal than on hippocampal synaptosomes, suggesting a possible heterogeneity of glycine sites recognized by HA 966 or different intrinsic activity in the two brain regions. The nanomolar potency of GV 150526A in reducing NMDA receptor function by competitively acting at the strychnine-insensitive glycine sites suggests that GV 150526A could be effective in vivo to reduce NMDA receptor over-stimulation, like in brain ischemia.

Animals↗
PubMed1997

Regulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice.

The role of the metabotropic glutamate receptor 1 (mGluR1) in synaptic plasticity was investigated in vivo in the intact hippocampus of mutant mice lacking this receptor. In a previous study we showed reduced long-term potentiation (LTP) in the dentate gyrus of mGluR1 -/- mice in vivo, but not when LTP was studied in a slice preparation. A possible explanation of this difference is that dentate neurons receive more inhibitory synaptic drive in vivo than in slice preparation where many inhibitory axon collaterals are lost. We report here that another form of synaptic plasticity, paired-pulse depression of the population spike, is also abnormal in the dentate gyrus of mGluR1-deficient mice when tested in vivo. In wild-type mice, stimulation of the medial perforant path produced paired-pulse depression of inter-pulse intervals (IPIs) up to 30 ms. Mutant mGluR1, on the other hand, showed a significantly longer IPI depression, up to 50 ms. Paired-pulse depression results from the activation of inhibitory interneurons. The GABA(B) agonist baclofen, acting presynaptically on the GABA interneurons, attenuated paired-pulse depression and allowed for a normal and stable LTP in mGluR1 mutant mice. These findings suggest an indirect role for mGluR1 in synaptic plasticity via a regulation of GABA inhibition.

Action Potentials↗
PubMed1997

Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site.

A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.

Animals↗
PubMed1997

The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat.

The neuroprotective activity of the novel, selective glycine antagonist GV150526 was assessed in the middle artery occlusion (MCAo) model of focal ischemia. Postischemia administration of GV150526 (3 mg/kg i.v.) up to 6 h post-MCAo resulted in a significant reduction of the infarct volume measured histologically 24 h later. The neuronal protection by GV150526 was accompanied by functionally significant protection determined by somatosensory evoked potential (SEP) responses recorded from the primary somatosensory cortex of rats under urethane anesthesia. Experimental occlusion of the MCA 7 days prior to electrophysiological testing induced a clear reduction in the SEP amplitude. GV150526 (3mg/kg, i.v.) was able to protect SEP responses recorded from the hindpaw cortical field in two groups of animals treated either 1 (n = 9) or 6 h (n = 10) post-MCAo. SEP responses recorded from the forepaw cortical field, an area closer to the core of the ischemic damage, were significantly protected only in the group treated 1 h post-MCAo. Histological evaluation of the rat brain regions showed a correlated decrease in the ischemic area of GV150526-treated groups. The volumes of the ischemic brains of both GV150526 groups were statistically different from the MCAo group (P < 0.05). These findings demonstrate that GV150526 is able to prevent the ischemic damage assessed histologically and affect the functional correlates of the ischemia evaluated by the electrophysiological SEP measurements.

Animals↗
PubMed1997

[Intrahepatic cholestasis: clinical and nosological classification. Critical survey of personal experience].

We reviewed 20 patients (16 females and 4 males) with intrahepatic cholestasis and recognised the following miscellaneous disorders: 12 primary biliary cirrhosis (PBC), 3 primary sclerosing cholangitis (PSC), 1 immune cholangiopathy (IC), 3 liver sarcoidosis and 1 cholestasis with Horton's arteritis. The aim of the study was to identify potentially differetiating clinical and biochemical findings in intrahepatic cholestasis. Sixty females were affected with changes reflecting a cholestatic pattern including an elevated alkaline phosphatasis and gammaglutamyltransferase level. Pruritus was found in 50 percent of PBC patients; fever addressed often, in liver sarcoidosis and Horton's arteritis. A striking increase of unesterified cholesterol was a common feature of PBC. An elevated polyclonal serum IgM in PBC such as in PSC. A circulating IgM antimitochondrial antibody and antinuclear antibodies were found in 90 percent of PBC patients; isolated antinuclear antibodies were detected in immune colangiopathy patients (IC). Liver biopsy was necessary to establish the diagnosis of intrahepatic cholestasis. Overlapping histopathologic features made diagnosis hard in cholestatic disorders, all but in liver sarcoidosis. Treatment with UDCA or TUDCA+/-colchicin, reduced cholestatic enzymes in 85 percent of PBC cohort, while it was unsuccessful in PSC-group. Steroid treatment was successful in sarcoidosis, Horton's arteritis and immune colangiopathy. Cy A did not improve clinical and biochemical features in PBC.

English Abstract↗
PubMed1997

[Comparison between torasemide and furosemide in the treatment of ascites in cirrhotic patients].

Twenty patients with cirrhosis and ascites were randomly divided in two groups to receive 20 mg/die of the new-loop-diuretic torasemide (T), and 50 mg/die of furosemide (F). All patients also received 200 mg/die of potassium canrenoate. Natriuretic and diuretic effects and consequent loss of weight were significantly better in the torasemide-group (T-group). Otherwise, loss of potassium and sodium/potassium ratio in urine were not significantly higher for T-group. Ammonium lowered with T and remained unchanged with F, but the difference was not statistically significant. No change was observed in blood-pressure, pulse-frequency, electrolyte plasmatic levels, azotemia, creatininemia and serum albumin. A significant increase of diuresis was obtained from the fourth day of treatment onwards by replacing F with T in the F-group. The T-group maintained T for eight days just to evaluate its efficacy and tolerability in the middle term: diuresis kept efficient and no side-effects occurred. This trial showed that T was a good and handy drug for cirrhosis with ascites whether as an alternative to F, or as a sequential treatment.

Ascites↗
PubMed1996

The microvascular system in ischemic cortical lesions.

In the rat, normal blood flow can be restored in the territory of the occluded artery after an arterial occlusion. This event has been attributed to changes in the collateral vessels supplying the territory of the occluded artery. Since only a limited amount of data is available about the plasticity of the microvascular system after a cortical ischemic lesion, in the present study we have evaluated whether the restoration of blood flow to normal levels in the territory of the middle cerebral artery after permanent ischemia is due only to flow through preexisting collateral vessels or also to the development of new microvessels. Middle cerebral artery occlusion was performed in 45 rats. After 24 h of ischemia, magnetic resonance imaging was used to select 16 rats with cortical lesions of similar size and location. After 2 weeks, vascular corrosion casts were obtained from 8 rats by injection of low-viscosity resin and observed by scanning electron microscopy. A correlative light and electron microscopy study was performed using the remaining 8 rats. Two different patterns of vascular modifications were found, one dorsal and one ventral to the lesion. The dorsal portion of the lesion was vascularized by collateral arteries originating from the anterior or posterior cerebral arteries. Collateral trunks showed a meandering course, mainly in the occipital pole. In the ventral portion of the lesion a complex microvascular system was found characterized by an intense vascular proliferation. The arterioles showed a parallel, candelabrum-like pattern with dichotomic branching. Contraction rings were frequently seen. The capillaries showed a sinusoid-like structure, with a large lumen and a continuous endothelium with many micropinocytotic vesicles. A peripheral ring-shaped venous sinus was composed of a network of flat vessels. These results give the first comprehensive description of the microvascular modifications in a focal model of infarct and suggest that the restoration of blood flow to normal levels described in the territory of the middle cerebral artery after permanent ischemia may be due not only to flow through collateral vessels but also to the development of a new vascular system originating mainly from branches of the middle cerebral artery before the occlusion point.

Animals↗
PubMed1996

Effects of the metabotropic glutamate receptor antagonist MCPG on spatial and context-specific learning.

The effects of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) on performance in a water maze and in context-specific associative learning were examined in rats previously implanted with cannulae. MCPG (20.8 micrograms) injected intraventricularly (i.c.v.) before testing impaired the performance of rats in the spatial version of the Morris water maze, but 1/10 of this dose did not. Memory retention, evaluated 24 hr post-training, was also affected by the high dose of MCPG. However, performance in a cued version of the water maze was not impaired by the high dose, excluding effects of the drug on perceptual faculties. The effects of the MCPG were further characterized on performance in another hippocampus-dependent spatial learning task, the context-dependent fear conditioning task. MCPG (20.8 micrograms, i.c.v.) did not interfere with conditioned freezing to context in this task. For comparison, a group of rats was injected with the NMDA receptor blocker MK801. MK801 at a dose that disrupted the performance in the spatial version of the Morris water maze (0.08 mg/kg), significantly reduced freezing compared to controls. These experiments indicate that MCPG-sensitive metabotropic receptors may be required for only a restricted subset of spatial learning tasks, while NMDA receptors may play an integral role in all spatial learning.

Animals↗
PubMed1996

[Orthotopic neobladder in women].

In women undergoing radical cystectomy for bladder cancer, orthotopic bladder reconstruction is now a viable alternative to urinary diversion: preservation of the external urethral sphincter by sectioning the urethra 0.5-1 cm distally to the bladder neck allows maintenance of urinary continence without compromising cancer control. 12 cases of bladder reconstruction in women operated on from 1986 to 1995 are presented here. A personal technique for the creation of an ileal neobladder is described: the use of staplers for detubularization of the ileum significantly reduces the operating time ("simplified ileal bladder"). Other important points of technique are as follows: 1. Careful preparation of the bladder neck and proximal urethra, staying above the pubo-urethral ligaments that must be preserved as the distal landmark of dissection; 2. "Nerve-sparing" isolation of the posterolateral wall of the bladder from the vagina; 3. Careful positioning of the pouch in the true pelvis, in order to avoid posterior prolapse of the neobladder. So far, results of bladder reconstruction in this series of patients are encouraging, both from a functional and oncological standpoint.

Cystectomy↗
PubMed1994

Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1.

Metabotropic glutamate receptor 1 (mGluR1) is a member of a large family of G-protein-coupled glutamate receptors, the physiological functions of which are largely unknown. Mice deficient in mGluR1 have severe motor coordination and spatial learning deficits. They have no gross anatomical or basic electrophysiological abnormalities in either the cerebellum or hippocampus, but they show impaired cerebellar long-term depression and hippocampal mossy fibre long-term potentiation. mGluR1-deficient mice should therefore be valuable models for studying synaptic plasticity.

Animals↗
PubMed1993

Qualitative and quantitative analysis of the progressive cerebral damage after middle cerebral artery occlusion in mice.

The middle cerebral artery occlusion (MCAO) in mice induces a focal cerebral ischaemia at the level of the tempo-parietal cortex. Histological staining and immunohistochemical markers were used to characterize the temporal progression of the cerebral infarct: both qualitative and quantitative analyses were performed at different days after the MCAO. At 3 days after MCAO, an extensive necrosis of the cerebral parenchyma was accompanied by extravasation and by massive oedema. After 7 days, GFAP marker showed a gliotic reaction with alteration of the astrocytes membrane permeability (S100 marker). Positivity for acid phosphatase staining indicated the presence of macrophages. At Day 14 and 21 following MCAO, the histological profile was essentially similar. Interestingly, at Day 7, 14 and 21, a previously unreported gliosis was observed in the subthalamic area. Quantitative analysis showed a significantly large infarct volume at Day 3 (7.88 +/- 1.95 mm3 +/- S.E.M.) compared to Day 7 (4.28 +/- 0.47 mm3 +/- S.E.M.). At Day 14 and Day 21 the infarct volumes were further decreased to 2.00 +/- 0.52 and 1.43 +/- 0.39 mm3 +/- S.E.M., respectively. These results suggest that it is important to consider the time of evaluation of cerebral ischaemia-induced cerebral infarct, especially in studies which aim to evaluate the neuroprotective effect of putative therapeutic agents.

Animals↗