High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept

Abstract

There are currently no clinically-efficacious drug therapies to treat brain damage secondary to traumatic brain injury (TBI). In this proof-of-concept study, we used a controlled cortical impact model of TBI in young adult rats to explore a novel promising approach that utilizes PNU-120596, a previously-reported highly selective Type-II positive allosteric modulator (α7-PAM) of α7 nicotinic acetylcholine receptors (nAChRs). α7-PAMs enhance and prolong α7 nAChR activation, but do not activate α7 nAChRs when administered without an agonist. The rational basis for the use of an α7-PAM as a post-TBI treatment is tripartite and arises from: 1) the intrinsic ability of brain injury to elevate extracellular levels of choline (a ubiquitous cell membrane-building material and a selective endogenous agonist of α7 nAChRs) due to the breakdown of cell membranes near the site and time of injury; 2) the ubiquitous expression of functional α7 nAChRs in neuronal and glial/immune brain cells; and 3) the potent neuroprotective and anti-inflammatory effects of α7 nAChR activation. Therefore, both neuroprotective and anti-inflammatory effects can be achieved post-TBI by targeting only a single player (i.e., the α7 nAChR) using α7-PAMs to enhance the activation of α7 nAChRs by injury-elevated extracellular choline. Our data support this hypothesis and demonstrate that subcutaneous administration of PNU-120596 post-TBI in young adult rats significantly reduces both brain cell damage and reactive gliosis. Therefore, our results introduce post-TBI systemic administration of α7-PAMs as a promising therapeutic intervention that could significantly restrict brain injury post-TBI and facilitate recovery of TBI patients.

Are positive allosteric modulators of α7 nAChRs clinically safe?

“…3 in (Ng et al 2007) and Figs 4 and 6 in (Williams et al 2012)]. This increase in cell viability is consistent with our own studies that demonstrated < 1 lM PNU120596 significantly reduced brain injury and neurological deficits after focal ischemia in a transient 90 min middle cerebral artery occlusion model of ischemic stroke in young adult rats Sun et al 2013), as well as significantly reduced brain cell damage and reactive gliosis after brain injury in a control cortical impact model of traumatic brain injury (Gatson et al 2015). A concentration of < 1 lM PNU120596 can be achieved in rodents shortly after intravenous 1 mg/kg (Hurst et al 2005) or subcutaneous 10-30 mg/kg (McLean et al 2012; administration.…”

Cholinergic modulation of the immune system presents new approaches for treating inflammation

“…TBI results in primary neuronal damage, which is unavoidable, and delayed secondary damage, which might be reduced by early therapeutic intervention (Gatson et al, 2015). In addition to causing primary neuronal damage, the initial insult to the brain activates microglial cells and astrocytes at the site of injury and triggers a systemic inflammatory response (Dash et al, 2016).…”

“…Studies using nicotine treatment as a therapeutic approach in experimental TBI showed no benefit, possibly due to desensitization of α7 receptors (Gatson et al, 2015; Kelso and Oestreich, 2012). However, recent work using the positive allosteric modulator PNU-120596 have yielded encouraging results (Gatson et al, 2015).…”

“…However, recent work using the positive allosteric modulator PNU-120596 have yielded encouraging results (Gatson et al, 2015). This agent works by enhancing the potency of the endogenous α7 receptor agonist, choline, which is elevated in the brain after TBI, while also decreasing receptor desensitization.…”

Development of [ 18 F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography

“…Non-invasive quantification of α7-nAChRs in humans would provide a better understanding of their role in various CNS disorders and could also simplify the development of nicotinic drugs for treatment of these disorders [27-32]. …”