Recent evidence suggests that the activation of the Jun N-terminal kinase (JNK) signal transduction pathway may be important in neuronal responses to stresses such as trophic factor deprivation. Preventing the activation of JNK and expression of c-Jun may, therefore, be neuroprotective. Here, we report that the small molecule CEP-1347, which has been shown to inhibit the JNK signalling pathway, promotes cholinergic activity in cultured embryonic septal neurones. In vivo, we have shown that CEP-1347, administered either by sub-cutaneous (s.c.) injection or by continuous infusion, is partially neuroprotective, for cholinergic neurones in the medial septum, following fimbria-fornix transection. These data suggest that small molecules such as CEP-1347 may have beneficial effects in treating neurodegenerative diseases.
Introduction:
Acute ischemic stroke (AIS) patients often have the head-of-bed (HOB) elevated to 30
0
while in the Emergency Department (ED). Flat HOB positioning has been shown to impact cerebral flow. Whether this holds true in undifferentiated, ED stroke patients is unknown.
Hypothesis:
We tested the hypothesis that 0
0
HOB positioning improves middle cerebral artery (MCA) mean flow velocity (MFV) in AIS compared to 30
0
. We secondarily tested the hypothesis that lower cardiac output (CO) is associated with greater fluctuation of MFV.
Methods:
This was a quasi-experimental study with repeat measurements of MCA MFV at 30
0
and 0
0
HOB position. Patients > 18 years presenting to the ED within 12 hours of symptom onset and a NIHSS ≥ 4 were eligible. After applying non-invasive monitoring of mean arterial pressure (MAP) and CO, an investigator used transcranial Doppler to obtain bilateral MCA MFV at 30
0
and 0
0
HOB position. If a signal was unobtainable on the ischemic side, the contralateral MFV was used for analysis. The primary analysis comprised all subjects with confirmed stroke on subsequent imaging and included student t-test for continuous measures. Secondary analysis used multiple linear regression to test if baseline NIHSS, age, MAP and CO were associated with changes in MFV.
Results:
There were 38 subjects enrolled, of whom 32 had confirmed AIS and were included in analysis. The mean age was 66 (±15) years and NIHSS 7 (±6). Stroke location was mixed (50% lacunar, 25% posterior and 25% anterior circulation). Averaged across all subjects, the MFV did not significantly increase when changing the HOB position from a 30
0
to 0
0
(+0.7 cm/s, 95% CI -1.6 to 3.1). Nevertheless, 16% (95% CI 5-33%) of subjects had a ≥ 20% increase and 47% (95% CI 29-65%) had any increase in MFV at 0
0
compared to 30
0
HOB. Adjusting for age, NIHSS and MAP, lower CO was associated with greater change in MFV (+2 cm/s [95% CI 0.2-3.7 cm/s] for every 1 L/min lower cardiac output, p=0.03).
Conclusions:
In conclusion, in a mixed sample of ED AIS patients, lower HOB position does not significantly impact cerebral flow on average, yet a considerable proportion of individuals may benefit from lower HOB position. Low cardiac output may identify those that benefit most.
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