Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-Type Glutamate Receptors Elicits Neuroprotection after Trimethyltin Exposure in Hippocampus

Munirathinam, Subramani; Rogers, Gary A.; Bahr, Ben A.

doi:10.1006/taap.2002.9534

Cited by 16 publications

(20 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synaptic and dendritic compromise is often found associated with calpain-induced cytoskeletal damage (Neumar et al, 2001;Bahr et al, 2002;Munirathinam et al, 2002). As shown here, AMPA-induced excitotoxic progression caused presynaptic and postsynaptic decline in the hippocampal slice model.…”

Section: Discussionsupporting

confidence: 62%

“…Cytoskeletal damage was assessed by measuring the calpainmediated spectrin breakdown product BDP N , a sensitive precursor to neuronal pathology in animal models of excitotoxic insults (Lee et al, 1991;Saido et al, 1993;Roberts-Lewis et al, 1994;Bahr et al, 1995Bahr et al, , 2002Saatman et al, 1996;Munirathinam et al, 2002;Zhu et al, 2005) and human brain injury (McCracken et al, 1999). AM374/AM404 reduced the excitotoxic damage induced in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

“…2C). Note that excitotoxic calpain activation is commonly associated with reductions in synaptic markers (Riederer et al, 1992;Vanderklish and Bahr, 2000;Bahr et al, 2002;Munirathinam et al, 2002;Karanian et al, 2005), and across slice samples, AM356 (Fig. 2B) and AM374/AM404 (Fig.…”

Section: Neuroprotection In Vitromentioning

confidence: 93%

See 2 more Smart Citations

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Karanian¹,

Brown²,

Makriyannis³

et al. 2005

J. Neurosci.

114

109

View full text Add to dashboard Cite

The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB 1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB 1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB 1 agonist AM356 (R-methanandamide). AM374/ AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB 1 -linked MAPK signaling, and (3) were blocked by a selective CB 1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB 1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Karanian¹,

Brown²,

Makriyannis³

et al. 2005

J. Neurosci.

114

109

View full text Add to dashboard Cite

show abstract

“…Blocking glutamatergic activity, especially through NMDA receptors, has also been shown to protect against ischemic insults in the cultured slices (Vornov et al, 1994;Newell et al, 1995;Strasser and Fischer, 1995;Pringle et al, 1997). Thus, the slice cultures have developed into a convenient system for studying not only mechanisms of toxicity but also effective avenues of neuroprotection (see Bahr, 1995;Breder et al, 2000;Ray et al, 2000;Munirathinam et al, 2002;Karanian et al, 2005;Noraberg et al, 2005). The past and present findings indicate that the slice model allows an avenue for studying mitochondrial toxicity in complex brain tissue and in the absence of systemic issues.…”

Section: Treatment Days Controlmentioning

confidence: 78%

“…2C; P < 0.001). Loss of synaptic markers is commonly linked to the pathogenic activation of the calcium-dependent protease calpain (see Munirathinam et al, 2002;Karanian et al, 2005). Correspondingly, the synaptic decline in Figure 2A was associated with calpain-mediated spectrin breakdown product BDP N (lane 2), an early and wellknown marker of excitotoxic cytoskeletal damage (Vanderklish and Bahr, 2000).…”

Section: Resultsmentioning

confidence: 96%

3-Nitropropionic acid toxicity in hippocampus: Protection throughN-methyl-D-aspartate receptor antagonism

et al. 2006

View full text Add to dashboard Cite

The over-activation of glutamate receptors can lead to excitotoxic cell death and is believed to be involved in the progression of neurodegenerative events in the vulnerable hippocampus. Here, we used an in vitro slice model to study toxicity produced in the hippocampus by the mitochondrial toxin 3-nitropropionic acid (3-NP). The organotypic slice cultures exhibit native cellular organization as well as dense arborization of neuronal processes and synaptic contacts. The hippocampal slices were exposed to 3-NP for 2-20 days, causing calpain-mediated breakdown of the spectrin cytoskeleton, a loss of pre- and postsynaptic markers, and neuronal atrophy. The N-methyl-D-aspartate (NMDA) receptor antagonist memantine reduced both the cytoskeletal damage and synaptic decline in a dose-dependent manner. 3-NP-induced cytotoxicity, as determined by the release of lactate dehydrogenase, was also reduced by memantine with EC50 values from 1.7 to 2.3 microM. Propidium iodide fluorescence and phase contrast microscopy confirmed memantine neuroprotection against the chronic toxin exposure. In addition, the protected tissue exhibited normal neuronal morphology in the major hippocampal subfields. These results indicate that antagonists of NMDA-type glutamate receptors are protective during the toxic outcome associated with mitochondrial dysfunction. They also provide further evidence of memantine's therapeutic potential against neurodegenerative diseases.

show abstract

Repeated contact with subtoxic soman leads to synaptic vulnerability in hippocampus

Munirathinam

Bahr

2004

J of Neuroscience Research

View full text Add to dashboard Cite

Soman, an anticholinesterase and dangerous nerve agent, produces convulsions, memory impairment, and cell loss in the brain, especially in the hippocampus. Soman-induced accumulation of acetylcholine initiates mechanisms responsible for the development of incapacitating seizures. The prolonged epileptiform nature of these seizures causes the release of another excitatory neurotransmitter, glutamate, which has been linked to the toxic action of the nerve agent. Here, we tested whether subtoxic soman exposures influence the brain's sensitivity to glutamate-based excitotoxicity. Over a 1-week period, hippocampal slice cultures were exposed daily to a transient level of soman that produced no evidence of synaptic deterioration. After the subtoxic soman treatments, however, the tissue became vulnerable to a brief episode of glutamate receptor overstimulation that normally resulted in little or no excitotoxic damage. In those slice cultures treated with subtoxic soman, a decline in synaptic markers as well as an increase in spectrin breakdown occurred 24 hr after the mild excitotoxic event. Exposure to high soman concentrations alone produced similar synaptic degeneration, but without evident cell death, suggesting that synaptic decline is an early neurotoxicological response to the nerve agent. Interestingly, enhanced excitotoxic sensitivity caused the brain tissue to become susceptible to disparate insults initiated before or after the soman contact. These findings indicate that seemingly innocuous soman exposures leave the hippocampus sensitive to the types of insults implicated in traumatic brain injury and stroke. They also warn that asymptomatic contact with soman may lead to progressive synaptopathogenesis and that early indicators of soman exposure are critical to prevent potential brain injury.

show abstract

Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-Type Glutamate Receptors Elicits Neuroprotection after Trimethyltin Exposure in Hippocampus

Cited by 16 publications

References 37 publications

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

3-Nitropropionic acid toxicity in hippocampus: Protection throughN-methyl-D-aspartate receptor antagonism

Repeated contact with subtoxic soman leads to synaptic vulnerability in hippocampus

Contact Info

Product

Resources

About