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BMC Neurosci
2015 Jun 19;16:67. doi: 10.1186/s12868-015-0208-9.
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Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia.
Luo J
,
Lee SH
,
VandeVrede L
,
Qin Z
,
Piyankarage S
,
Tavassoli E
,
Asghodom RT
,
Ben Aissa M
,
Fà M
,
Arancio O
,
Yue L
,
Pepperberg DR
,
Thatcher GR
.
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Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.
Fig. 1. Retention of GABAA potentiating, and attenuated sedative activity in NMZ relative to CMZ. a Oocytes expressing the α1β2γ2 GABAA receptor (n = 6) showed a dose response to increasing concentrations of NMZ in the presence of GABA (6 µM). Addition of picrotoxin (200 µM) caused 96 ± 2 % inhibition of the potentiated GABA response (n = 4) (O). Data show mean ± SD normalized to the saturated 200 µM GABA response. b Male C57Bl/6 mice (n = 5–16) were injected i.p. with CMZ (45 mg/kg) or an equimolar dose of NMZ before testing for their latency to fall on a rotating rod (RR). NMZ showed less sedation than CMZ at various time points. Data show mean ± SEM. Statistical significance relative to vehicle is indicated by *p < 0.05, **p < 0.01, ***p < 0.001, using one-way ANOVA with Dunnett’s post hoc test. c Male C57BL/6 mice (n = 4–5) were injected with escalating doses of CMZ and NMZ and loss of righting reflex (LORR) was measured over 2 h. NMZ showed less sedation than CMZ, and no LORR was observed for NMZ until 125 mg/kg. Data show mean ± SEM. Non-zero statistical significance by one-sample t test is indicated by *p < 0.05, ***p < 0.001
Fig. 2. Reversal of induced amnestic deficits by multiple agents in STPA. a Male C57BL/6 mice (n = 5–10) treated with vehicle or NMZ (1 mg/kg, single dose i.p.; or 20 mg/kg/day, oral drinking water) after being administered with diverse amnestic agents were tested for their latency to enter the dark side of the STPA apparatus at 24 h after training. NMZ reversed memory deficits induced by scopolamine (1 mg/kg), MK-801 (0.1 mg/kg), diazepam (0.5 mg/kg), and L-NAME (50 mg/kg). b Male C57BL/6 mice with scopolamine-induced deficits treated with NMZ showed reversal of latency to enter the dark side of the chamber 24 and 48 h after training. Statistical significance is indicated by ***p < 0.001 compared with the respective saline control for each time point, using unpaired t test. c In scopolamine induced deficits, NMZ demonstrated reversal of cognitive deficits when administered i.p. between 40 min prior to training (−40 min) and 90 min after training (+90 min); but no significant effect was observed when administered 60 or 120 prior to training. Data show mean ± SEM. Statistical significance is indicated by *p < 0.05, **p < 0.01, ***p < 0.001 compared with the respective saline control for each treatment, using one-way ANOVA with Dunnett’s post hoc test
Fig. 3. Pharmacokinetics study on male C57BL/6 mice treated with NMZ, single dose (50 or 1 mg/kg, i.p.) or supplied in hydrogel (20 mg/kg/day), showing bioavailability in brain and plasma at various time points after initiation of treatment. The estimated t½ for i.p. administration is 10 min
Fig. 4. Beneficial effects seen in LTP from NMZ treatment in APP/PS1 mice. a, b LTP was measured in the CA1 region of hippocampal sections in 4 month old male APP/PS1 mice or littermate controls (n = 5–8) treated with CMZ (a) or NMZ (b). NMZ showed restoration of LTP in APP/PS1 mice to WT levels, whereas the effects of CMZ were not significant. Statistical significance was analyzed by two-way ANOVA with repeated measures: WT veh (n = 6) vs. WT NMZ (n = 6): F(1,10) = 1.106 p > 0.05 No Sig.; WT veh vs. APP/PS1 veh: F(1,12) = 18.86 p < 0.05 Sig; APP/PS1 veh (n = 8) vs. APP/PS1 NMZ (n = 7): F(1,13) = 17.71 p < 0.05 Sig; WT NMZ vs. APP/PS1 NMZ: F(1,11) = 0.02351 p > 0.05 No Sig
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