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000285015 1001_ $$aTessitore, Sara$$b0
000285015 245__ $$aFocus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?
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000285015 520__ $$aAmyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. Evidence indicates that ALS is a 'multifactorial' and 'multicellular' disease; however, the causes of ALS remain elusive, as the mechanisms underlying the disease have not yet been completely clarified. One major proposed mechanism, first described in 1990, is the glutamate excitotoxicity theory. This theory suggests that excessive glutamatergic neurotransmission, combined with impaired glutamate clearance, significantly contributes to motor neuron degeneration. Aberrant glutamate neurotransmission may lead to precocious motor neuron hyperexcitability in the brain cortex and spinal cord, which can be later followed by hypoexcitability phases. Accumulating evidence suggests that impairment in inhibitory neurotransmission is relevant for excitation/inhibition imbalance, leading to excitotoxicity, a critical feature of ALS. Gamma-aminobutyric acid (GABA) and glycine are the primary inhibitory neurotransmitters that modulate neuronal excitability, including that of motor neurons. In ALS, dysfunction of inhibitory processes and loss of cortical and spinal inhibitory interneurons are observed. Renshaw cells, which mediate recurrent inhibition in the spinal cord, seem particularly vulnerable. The interactions among neurotransmitters, including glutamate, GABA, and glycine, play pivotal roles in regulating the excitation/inhibition balance. Auto- or hetero-receptor-mediated interactions are crucial, but auto- or hetero-transporter-mediated neurotransmission control, as well as other molecular mechanisms that regulate neuronal interplay, are also relevant, as they can be altered in pathological conditions such as ALS. To facilitate the search for new effective therapies for ALS, attention toward the impairment of inhibitory neurotransmission is essential to determine the role of excitation/inhibition imbalance on excitotoxicity. Different pharmacological agents are being used to treat other pathologies in which the excitation/inhibition ratio is impaired. Among these, we highlighted the potential of novel glycine and GABA receptor ligands and transporter inhibitors, as stand-alone interventions or in combination with other treatments. The present review aims to elucidate the complex interplay between excitatory and inhibitory neurotransmission in ALS, exploring the potential to target this imbalance for therapeutic purposes.
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000285015 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000285015 650_7 $$2Other$$aCortex
000285015 650_7 $$2Other$$aExcitation/inhibition balance
000285015 650_7 $$2Other$$aGABA
000285015 650_7 $$2Other$$aGlutamate
000285015 650_7 $$2Other$$aGlycine
000285015 650_7 $$2Other$$aIon channels
000285015 650_7 $$2Other$$aReceptors
000285015 650_7 $$2Other$$aSpinal cord
000285015 650_7 $$2Other$$aTransporters
000285015 650_7 $$03KX376GY7L$$2NLM Chemicals$$aGlutamic Acid
000285015 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: physiopathology
000285015 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000285015 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: drug therapy
000285015 650_2 $$2MeSH$$aHumans
000285015 650_2 $$2MeSH$$aSynaptic Transmission: physiology
000285015 650_2 $$2MeSH$$aAnimals
000285015 650_2 $$2MeSH$$aMotor Neurons: metabolism
000285015 650_2 $$2MeSH$$aMotor Neurons: physiology
000285015 650_2 $$2MeSH$$aGlutamic Acid: metabolism
000285015 650_2 $$2MeSH$$aNeural Inhibition: physiology
000285015 7001_ $$aTorazza, Carola$$b1
000285015 7001_ $$aBonifacino, Tiziana$$b2
000285015 7001_ $$aBacchetti, Francesca$$b3
000285015 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b4$$udzne
000285015 7001_ $$aRaiteri, Luca$$b5
000285015 7001_ $$aMilanese, Marco$$b6
000285015 7001_ $$aBonanno, Giambattista$$b7
000285015 773__ $$0PERI:(DE-600)1471408-5$$a10.1016/j.nbd.2026.107272$$gVol. 219, p. 107272 -$$p107272$$tNeurobiology of disease$$v219$$x0969-9961$$y2026
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