Abstract: Decreased neuronal survival-signaling and brain damage: Stroke is a leading cause of death worldwide, the major cause of adult disability and second of dementia. In spite of the social and economic importance of this disorder, and after intense research, no effective drugs have yet reached the clinic. Blood reperfusion with the thrombolytic agent tissue plasminogen activator remains the only pharmacologic treatment currently available for ischemic stroke, the major type of brain infarction (> 85% of total cases). Damage in this situation results from thrombotic or embolic occlusion of a cerebral artery causing a decrease of blood flow to a specific area of the brain parenchyma, neurons being particularly sensitive to a reduction of the supply of glucose and oxygen. It is thus a priority to develop neuroprotective strategies able to preserve neurons from the ischemic injury and, in this way, reduce brain damage and patient disability. A promising approach involves rescue of the area of penumbra surrounding the infarct, a region functionally silent but structurally intact. However, neurons in the penumbra can undergo a process of delayed death known as excitotoxicity, caused by overstimulation of the N-methyl-D-aspartate type of excitatory glutamate receptors (NMDARs). The critical role played by these receptors in synaptic plasticity, learning and memory, together with dual functions in neuronal survival and death (Hardingham et al., 2002), underlies previous failure of NMDAR blockade as a therapeutic target in stroke. Nevertheless, the low-affinity uncompetitive NMDAR antagonist memantine is still able to improve cognitive functions and behavioral disturbances in moderate-to-severe Alzheimer’s disease, a neurodegenerative disorder also associated with excitotoxicity. Anyhow, for stroke treatment, we are currently exploring alternative strategies such as the inhibition of neurotoxic proteins that act downstream overactivated NMDARs or directed to enhance neuronal survival pathways. Concerning the latter, several laboratories have chosen to analyze the promotion of neurotrophin-dependent survival pathways by treatment with brain-derived neurotrophic factor (BDNF) as a possible strategy for neuroprotection in stroke but also other acute or chronic disorders of the central nervous system. However, a potential caveat of this approach is that signaling mediated by BDNF is dramatically subverted by excitotoxicity, a process not only central to stroke but, as mentioned, also associated to many other neurological disorders (Tejeda and Diaz-Guerra, 2017). In models of stroke and human samples, excitotoxicity induces transcriptional and proteolytic mechanisms strongly associated with neurodegeneration that alter the expression of the two major brain isoforms of the BDNF receptor, tropomyosin-related kinase B (TrkB): the catalytically active full-length receptor (TrkB-FL) and a truncated receptor lacking the tyrosine kinase domain (TrkB-T1) (Vidaurre et al., 2012; Tejeda et al., 2016). Nonetheless, recent work from my group has demonstrated that it is possible to interfere TrkB-FL degradation in stroke and, in this way, decrease neuronal death and brain damage (Tejeda et al., 2019). Interestingly, these results have been accomplished by primarily preventing TrkB-FL endocytosis, which is strongly induced by excitotoxicity and precedes receptor processing (Figure 1). In this perspective, we will discuss the prospects of using the modulation of excitotoxicity-induced endocytosis, and the subsequent preservation of membrane survival proteins, as a neuroprotective therapeutic strategy for acute brain insults (stroke, epilepsy, or trauma) and excitotoxicity-associated chronic disorders (e.g., Alzheimer’s, Parkinson´s, Huntington´s diseases).