Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain

Dicou, Eleni; Rangon, Claire-Marie; Guimiot, Fabien; Spedding, Michael; Gressèns, Pierre

doi:10.1016/s0006-8993(03)02357-6

Cited by 71 publications

(38 citation statements)

References 14 publications

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“…There is far less information on the protective value of increasing endogenous BDNF levels. However, reports of greater vulnerability to ischemia (Endres et al, 2000) and ethanol exposure (Heaton et al, 2002) in transgenic mice with low (or no) BDNF expression, and of reduced ibotenate-induced cell death after ampakine pretreatment and increases in endogenous BDNF (Dicou et al, 2003), suggest that the endogenous factor is protective and that levels of protection covary with protein content. An important goal of future research will be to test the integrity of tyrosine kinase B expression and signaling with prolonged ampakineinduced increases in BDNF protein content and the neuroprotective value of this manipulation.…”

Section: Discussionmentioning

confidence: 99%

“…An alternative approach would be to pharmacologically elevate the production of endogenous BDNF. Recent studies have shown that marked elevations in BDNF expression can be achieved in vitro and in vivo using ampakines Legutko et al, 2001;Mackowiak et al, 2002;Dicou et al, 2003); these compounds belong to several chemical families and cause minimal physiological or behavioral disturbances in animals or humans. These results suggest that neuroprotective treatments based on elevated levels of endogenous BDNF are feasible.…”

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confidence: 99%

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Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Lauterborn

Truong²,

Baudry³

et al. 2003

J Pharmacol Exp Ther

124

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The ampakine CX614 positively modulates ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor (BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases BDNF gene expression but with time, mRNA levels fall despite the continued presence of active drug. The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h) treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546) did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity. Finally, using a "24-h on/24-h off" CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF mRNA was induced with each ampakine application, and elevated BDNF protein levels were maintained through 5 days in vitro. These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Lauterborn

Truong²,

Baudry³

et al. 2003

J Pharmacol Exp Ther

124

View full text Add to dashboard Cite

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“…a predominance of grey matter damage): (1) a hypoxic-ischaemic model produced by the combination of global hypoxia with a unilateral carotid artery ligation at postnatal day 7 in rats or day 9 in mice; 54,55 and (2) a model of excitotoxic brain damage produced by intracerebral injection of newborn mice or rats with the glutamatergic analogue ibotenate. 56,57 In the hypoxic-ischaemic model, systemic injection of low and non-injurious doses of a toll-like receptor (TLR) 4 or TLR3 agonist (Escherichia coli-derived lipopolysaccharide [LPS] or polyinosinic:polycytidylic acid, respectively), 4 hours before a typically non-injurious hypoxic-ischaemic insult (lasting 20min), induced massive hemispheric brain damage. 21,58 Administering an agent with anti-inflammatory properties, or disabling the TLR inflammatory pathway, reduced the severity of the LPS sensitization.…”

Section: Experimental Evidence Of Inflammation-induced Sensitization mentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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“…[3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression.…”

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confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy. Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression. 9,10 Positive AMPA receptor modulators however are preferred over direct administration of BDNF itself as this class of molecules readily crosses the blood-brain barrier. 11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.Growth-associated protein-43 (GAP-43) is a nervous system specific F-actin regulating phosphoprotein expressed during de...

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Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain

Cited by 71 publications

References 14 publications

Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Inflammation‐induced sensitization of the brain in term infants

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

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