Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655

Szabados, Tamás; Gigler, Gábor; Szikora, István; Gyertyán, István; Lévay, György

doi:10.1016/s0361-9230(01)00516-0

Cited by 43 publications

(24 citation statements)

References 17 publications

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“…1 A). The electrophysiological response of reinnervated muscles resistant to vecuronium application was subsequently blocked by the glutamate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist (AMPA) receptor antagonist GYKI 52466 (19,20), administered at 10 mg͞kg i.p. (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The pharmacological analysis of receptors involved in activation of reinnervated NMJ strikingly indicates the presence and function of AMPA-type GluRs. We show that the muscle response to nerve stimulation was totally blocked by the selective AMPA receptor antagonist GYKI 52466 (19,20). Because AMPA receptors are tetrameric heteromeric complexes of four homologous subunits, GluR1-4, we analyzed the expression of each AMPA receptor gene.…”

Section: Discussionmentioning

confidence: 99%

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Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Brunelli

Spano

Barlati

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Acetylcholine is the main neurotransmitter at the mammalian neuromuscular junction (NMJ) where nicotinic acetylcholine receptors mediate the signaling between nerve terminals and muscle fibers. We show that under glutamatergic transmission, rat NMJ switches from cholinergic type synapse to glutamatergic synapse. Connecting skeletal muscle to the lateral white matter of the spinal cord by grafting the distal stump of the transected motor nerve produced functional muscle reinnervation. The restored neuromuscular activity became resistant to common curare blockers but sensitive to the glutamate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Analysis of the regenerated nerve disclosed new glutamatergic axons and the disappearance of cholinergic fibers. Many axons belonged to the supraspinal neurons located in the red nucleus and the brainstem nuclei. Finally, the innervated muscle displayed high expression and clustering of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits glutamate receptors 1 and 2. Our data suggest that supraspinal neurons can target skeletal muscle, which retains the plasticity to generate functional glutamatergic NMJ.glutamate ͉ neuromuscular junction ͉ red nucleus T raumatic paraplegia caused by spinal cord injury is still an irreversible condition. So far, there is no medical or surgical treatment capable of curing paraplegia. The CNS is ''nonpermissive'' for the advancement of injured axons because of an abundance of growth-inhibitory molecules in the myelin and the glial scar (1-3). In addition, there are no growth-promoting factors at the neuronal growth cone or at the somata. However, when peripheral nerves (PN) are directly grafted into the CNS, central axons can progress throughout the peripheral endoneural tubes, suggesting they can regenerate in an appropriate environment (4-7). The central fibers that are diverted into a nerve graft implanted within a healthy structure derive from neurons axotomized during the grafting procedure and not from uninjured neurons spared by nerve graft implantation (8). Regrowth ceases as soon as axons contact the CNS milieu again. Various studies have demonstrated that central axons can elongate within autologous PN grafted into the spinal cord and form functional synapses with skeletal muscles, leading to motor and sensory recovery (7, 9-11). Spinal cord neurons, as well as the midbrain and brainstem neurons that originate the rubrospinal, vestibulospinal, and reticulospinal tracts, are endowed with a high capability of axonal regeneration into PN transplants (12-15). Thus, in an attempt to bypass a spinal cord lesion by connecting descending motor fibers with skeletal muscles, muscular nerve branches were inserted into the severed lateral bundle of monkey spinal cord (11). The new connection produced muscle reinnervation and restored motor function. This result raised the possibility that the regrowth of axons descending from central noncholinergic neurons and cut during the grafting procedure could be re...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Brunelli

Spano

Barlati

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…14 In addition to the stroke models described earlier, TLP has been evaluated in a model of traumatic brain injury in rats. Talampanel was administered orally as a suspension 1 h before the seizure stimulus.…”

Section: Neuroprotective Effects Of Tlp In Animalsmentioning

confidence: 99%

Talampanel

Howes¹,

Bell²

2007

Neurotherapeutics

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“…AMPA receptor antagonists are very effective anticonvulsants in animal seizure models (Lees, 2000;Szabados et al, 2001). Since children with juvenile Batten disease also suffer from frequent occurrence of seizures, therapeutic application of an AMPA receptor antagonist could improve their motor skills and prevent seizure development, as well.…”

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confidence: 99%

Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease

Kovács

Pearce

2008

Experimental Neurology

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Juvenile Batten disease, caused by mutations in the CLN3 gene, is a fatal, incurable neurodegenerative disorder in children. The Cln3-loss-of-function (Cln3 Δex1-6 ) mouse model of the disease exhibits many characteristic pathological features of the human disorder including a deficit in motor skills. Our recent findings (Kovács et al., 2006) suggested that the neurological deficit in the Cln3 Δex1-6 mouse model of the disease might result from an abnormally increased AMPA receptor activity in the cerebellum. Therefore, we tested if administration of low doses of an AMPA receptor antagonist, that attenuate AMPA receptor function but avoid a toxic, complete blockade of the receptor, have beneficial effects in Cln3 Δex1-6 mice. Here we show that attenuation of AMPA receptor activity by a single intraperitoneal injection of the non-competitive AMPA antagonist, EGIS-8332 (1 mg/kg), significantly improves the motor skills of Cln3 Δex1-6 mice. Our results provide a new, promising therapeutic approach for juvenile Batten disease.

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Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655

Cited by 43 publications

References 17 publications

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Talampanel

Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease

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