Fig. 1.

Schematic illustration of how the α2A-AR agonist, guanfacine, and the anti-oxidant NAC, can have therapeutic effects in treating the symptoms of TBI and long-COVID by strengthening PFC neurotransmission and synaptic connections and reducing neuroinflammation. Layer III dlPFC microcircuits depend on NMDAR synapses on dendritic spines to produce the persistent neuronal firing needed for higher cognition. Inflammation drives the production of kynurenic acid, generated from kynurenine by KAT II, which blocks NMDAR and markedly reduces dlPFC neuronal firing. These synapses are also weakened by the opening of nearby potassium (K⁺) channels by high levels of cAMP-calcium signaling (Arnsten et al., 2021). Stressors increase catecholamine release in the PFC, which stimulates α1-AR and D1R to drive intracellular calcium-cAMP-PKA signaling (Arnsten et al., 2021). This in turn opens K⁺ channels to weaken synaptic efficacy, reduce neuronal firing, and impair working memory and executive functioning. With sustained stress, calcium overloads mitochondria driving a MOAS phenotype, and the initiation of complement C1q signaling, which communicates to microglia to remove spines and dendrites (phagocytosis), leading to loss of PFC gray matter. Guanfacine and NAC can reduce many of these harmful actions: NAC can inhibit KAT II to reduce kynurenic acid production, restoring NMDR neurotransmission, while the α2A-AR agonist, guanfacine, inhibits cAMP-PKA signaling in spines to reduce calcium dysregulation and close K⁺ channels, strengthening network connectivity. These agents can also reduce neuroinflammatory actions: NAC reduces calcium overload of mitochondria, and guanfacine deactivates microglia to reduce phagocytosis. Note that α2A-AR have high affinity for NE and are thus engaged under nonstress conditions with modest levels of NE release, while α1-AR have low affinity for NE and thus are engaged under conditions of stress when there are high levels of NE release (Arnsten et al., 2021). NMDAR=NMDA glutamate receptors; MOAS=mitochondria-on-a-string which are associated with calcium overload; KAT II=kynurenine aminotransferase.