Examining protection from anoxic depolarization by the drugs dibucaine and 2 carbetapentane using whole - cell recording from CA 1 neurons 3 4 Sean

28 As an immediate consequence of stroke onset, failure of the Na/KATPase pump evokes a 29 propagating anoxic depolarization (AD) across gray matter. Acute neuronal swelling and dendritic 30 beading arise within seconds in the future ischemic core, imaged as changes in light transmittance (ΔLT). 31 AD is itself not a target for drug-based reduction of stroke injury because it is generated in the first 32 minutes of stroke onset. Peri-infarct depolarizations (PIDs) are milder AD–like events that recur during 33 the hours following AD and contribute to infarct expansion. Inhibiting PIDs with drugs could limit 34 expansion. Two types of drugs, ‘caines’ and sigma-1 receptor ligands, have been found to inhibit AD 35 onset (and may also oppose PID initiation) yet their underlying actions have not been examined. 36 Imaging ΔLT in the CA1 region simultaneously with whole-cell current-clamp recording from 37 CA1pyramidal neurons reveal that the elevated LT front and onset of the AD are coincident. Either 38 dibucaine or carbetapentane pretreatment significantly delays AD onset without affecting resting 39 membrane potential or neuronal input resistance. Dibucaine decreases excitability by raising spike 40 threshold and decreasing action potential (AP) frequency, whereas carbetapentane eliminates the fast 41 afterhyperpolarization, while accentuating the slow afterhyperpolarization to reduce AP frequency. 42 Orthodromic and antidromic APs are eliminated by dibucaine within 15 min, but not by carbetapentane. 43 Thus, both drugs reduce cortical excitability at the level of the single pyramidal neuron, but through 44 strikingly different mechanisms. In vivo both drugs would likely inhibit recurring PIDs in the expanding 45 penumbra, and so potentially could reduce developing neuronal damage over many hours post-stroke 46 when PIDs occur. 47