Alterations in Cholinergic Pathways and Therapeutic Strategies Targeting Cholinergic System after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) results in varying degrees of disability in a significant number of persons annually. The mechanisms of cognitive dysfunction after TBI have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noradrenergic dysfunction has been described in many previous reports. In addition, cholinergic dysfunction has also been a familiar topic among TBI researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in previous studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction after TBI. In addition, we describe studies that use both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies.

Keywords: acetylcholine; cholinergic; nicotinic; traumatic brain injury.

FIG. 1.

Muscarinic acetylcholine receptor (AChR) regulation of ACh regulating enzymes. Activation of M₁, M₃, and M₅ are excitatory, leading to activation of phospholipase C (PLC), then subsequent calcium mediated C-Fos activation. This upregulates acetylcholinesterase (AChE) expression and downregulates choline acetylransferase (ChAT) and vesicular ACh transporter (vAChT) expression. Activation of M₂ and M₄ are inhibitory, however, and can inhibit cyclic AMP (cAMP) mediated signaling. Color image is available online at www.liebertpub.com/neu

FIG. 2.

Activation of nicotinic α7 receptor and its effects. There are multiple effects of α7 receptor activation, including downstream pathways activating long-term potentiation as well as anti-apoptotic effects. In microglia, there is inhibition of pro-inflammatory cytokine expression. Color image is available online at www.liebertpub.com/neu