October 18, 2019 by freemexy
Bumetanide Prevents Brain Trauma-Induced Depressive-Like Behavior
Brain trauma triggers a cascade of deleterious events leading to enhanced incidence of drug resistant epilepsies, depression, and cognitive dysfunctions. The underlying mechanisms leading to these alterations are poorly understood and treatment that attenuates those sequels are not available. Using controlled-cortical impact as an experimental model of brain trauma in adult mice, we found a strong suppressive effect of the sodium-potassium-chloride importer (NKCC1) specific antagonist bumetanide on the appearance of depressive-like behavior. We demonstrate that this alteration in behavior is associated with an impairment of post-traumatic secondary neurogenesis within the dentate gyrus of the hippocampus. The mechanism mediating the effect of bumetanide involves early transient changes in the expression of chloride regulatory proteins and qualitative changes in GABA(A) mediated transmission from hyperpolarizing to depolarizing after brain trauma. This work opens new perspectives in the early treatment of human post-traumatic induced depression. Our results strongly suggest that bumetanide might constitute an efficient prophylactic treatment to reduce neurological and psychiatric consequences of brain trauma.Bumetanide powder
In a wide range of neurological and psychiatric disorders, GABAergic signaling is affected through chloride homeostasis impairment triggered by a down regulation of the main neuronal-specific chloride and potassium extruder, KCC2, and up regulation of the chloride importer NKCC1, respectively (Medina et al., 2014). Similar changes in GABAergic transmission have been reported in a different model of brain trauma (Ben-Ari, 2017). This leads to depolarization and also an excitatory action of GABA that could perturb the generation of behaviorally relevant oscillations and integrative properties of brain networks (Rivera et al., 1999; Luscher et al., 2011; Kahle et al., 2013; Medina et al., 2014; Ben-Ari, 2017). These shifts have been observed notably in developmental disorders including autism spectrum disorders (ASDs) (Tyzio et al., 2014), stroke (Jaenisch et al., 2010; Xu et al., 2016) and epilepsy (Pallud et al., 2014; Tyzio et al., 2014; Kelley et al., 2016). The interaction between major depressive disorders (MDDs) and GABAergic neurotransmission has been suggested in a genetic mice model of GABA(B)-R knock-out (Mombereau et al., 2005) and in studies showing an antidepressant effect of potent and selective blockage of GABA(A) transmission (Rudolph and Knoflach, 2011) at both the hippocampus (Boldrini et al., 2013) and mesolimbic system (Kandratavicius et al., 2014). In addition, several observations link chloride homeostasis to secondary neurogenesis through GABA(A) neurotransmission (Luscher et al., 2011; Ostroumov et al., 2016). The generation of new neurons within the DG requires different steps: first, the transition from quiescent to proliferative progenitors, then their differentiation to immature neurons in a GABAergic-dependent manner (Chell and Frisén, 2012; Moss and Toni, 2013). In that context, it's well-accepted that brain trauma alters neurogenesis (Perry et al., 2015; Stein et al., 2015). In the past decade, the relationship between GABA neurotransmission and neurogenesis has been well-established. Ge and collaborators have shown that GABA receptors are expressed in the progenitor cells and that GABA itself, either ambient or synaptically-released GABA, could act at different steps during neurogenesis from proliferation to cell differentiation and finally synaptic integration (Ge et al., 2006; Anacker and Hen, 2017). In addition, the GABAergic polarity acts on the cell integration (Ge et al., 2006) but also in cell proliferation (Sun et al., 2012), thus establishing a causal link between cell cycling and cell cycle exit on depolarizing GABA condition (Scharfman and Bernstein, 2015; Hu J.J. et al., 2017). Apart from the monoamine hypothesis, a new theory based on the GABA release itself has been proposed to contribute to depression. GABA release has been demonstrated to be impaired in psychiatric disorders and particularly in depression (Luscher et al., 2011; Gabbay et al., 2012). More particularly, the GABAergic receptors have been shown to be decreased in expression and function in the dentate gyrus of depressed patients (Luscher et al., 2011; Lüscher and Fuchs, 2015) and brain tissues collected from suicide patients with a history of depression and anxiety (Merali et al., 2004). One of the first phenomenon linking depression and the hippocampus is the change in hippocampal volume observed both in rodent and in human (Savitz et al., 2010; Schuhmacher et al., 2013; Roddy et al., 2018). This is a common trait observed when the hypothalamic-pituitary-adrenal (HPA) axis is impaired. Other brain regions such as cingulate cortex, prefrontal cortex or even amygdala are also associated with depression (Drevets et al., 2008). In addition to volume changes other functions are changed in the hippocampus of animal displaying DLB, e.g., modified volume (Roddy et al., 2018), impaired GABAergic function (Merali et al., 2004), increase in excitability and monoamine dysfunction (Samuels et al., 2015) as well as impaired secondary neurogenesis and cognitive deficit (Ferguson et al., 2016; Anacker and Hen, 2017). Taken together, this makes the hippocampal formation a important and valuable structure to study depression in TBI models.
Parvalbumin-containing interneurons are the principal source of GABA release within the dentate gyrus and thus potential candidates to explain controlled-cortical impact (CCI)-induced dysregulations through their role in the synchronicity of hippocampal networks (Curia et al., 2008; Drexel et al., 2011; Shiri et al., 2014). Moreover, it is accepted that the activity of this class of interneurons could act on secondary neurogenesis by providing a source of ambient GABA (Song et al., 2012; Butler et al., 2016; Hu D. et al., 2017; Pérez-Domínguez et al., 2017), but little is known about the relationship that exists between parvalbumin-containing interneurons and the establishment of post-traumatic depression (Earnheart et al., 2007; Luscher et al., 2011; Fenton, 2015). Moreover, in human depression, their action is far from being established (Khundakar et al., 2011; Pehrson and Sanchez, 2015; Smiley et al., 2016).
Interestingly, the NKCC1 chloride importer antagonist bumetanide has been shown to attenuate many disorders like ASD, Parkinson's disease, and schizophrenia as well as some CCI-induced consequences. This stresses the therapeutic potential of restoring low (Cl-)i levels and an efficient GABAergic inhibition (Lemonnier et al., 2013, 2016; Damier et al., 2016; Xu et al., 2016; Ben-Ari, 2017). Although, it has been previously shown that bumetanide could have various positive effects on TBI models (Hui et al., 2016; Zhang et al., 2017) and could also act on secondary neurogenesis in stroke condition (Xu et al., 2016), yet nothing is known about the early action of this compound prior to the establishment of depressive-like behaviors (DLB). Our results showed that brain trauma disrupts chloride homeostasis, leading to hippocampal network disturbances and impaired neurogenesis associated with DLB. Early restoration of chloride homeostasis, using the NKCC1 inhibitor bumetanide rapidly after trauma, attenuates the severity of post-traumatic alterations notably by reducing interneuron loss. This, taken together, suggests a therapeutic potential of this FDA-approved compound after trauma.