Diabetes Mellitus to Neurodegenerative Disorders: Is Oxidative Stress Fueling the Flame?

BACKGROUND & OBJECTIVE: Diabetes and neurodegenerative diseases (ND) are progressive morbidities and represent a major public health burden. A growing body of evidence points towards the comorbidity of diabetes and NDs with a possible exacerbation of latter by former. Considering the high prevalence of both morbidities in aging world population, even a modest impact of diabetes on NDs could lead to significant public health implications. Several hypotheses and mechanistic evidence were proposed linking altered glucose metabolism to the risk of progressive dementia. Unregulated production of reactive oxygen species (ROS) and resultant oxidative stress (OS) are the common features of diabetes as well as NDs. CONCLUSION: This review explores the concept of altered glucose metabolic pathways leading to ROS increase and its possible link to NDs, with a special emphasis on Alzheimer's diseases (AD). We also discuss the detailed mechanistic link between hyperglycemia, ROS generation, and neurodegeneration to highlight potential therapeutic avenues for better prevention and treatment.

Endothelin-1 Decreases Excitability of the Dorsal Root Ganglion Neurons via ETB Receptor.

Endothelin-1 (ET-1) has been demonstrated to be a pro-nociceptive as well as an anti-nociceptive agent. However, underlying molecular mechanisms for these pain modulatory actions remain unclear. In the present study, we evaluated the ability of ET-1 to alter the nociceptor excitability using a patch clamp technique in acutely dissociated rat dorsal root ganglion (DRG) neurons. ET-1 produced an increase in threshold current to evoke an action potential (I threshold) and hyperpolarization of resting membrane potential (RMP) indicating decreased excitability of DRG neurons. I threshold increased from 0.25 ± 0.08 to 0.33 ± 0.07 nA and hyperpolarized RMP from -57.51 ± 1.70 to -67.41 ± 2.92 mV by ET-1 (100 nM). The hyperpolarizing effect of ET-1 appears to be orchestrated via modulation of membrane conductances, namely voltage-gated sodium current (I Na) and outward transient potassium current (I KT). ET-1, 30 and 100 nM, decreased the peak I Na by 41.3 ± 6.8 and 74 ± 15.2%, respectively. Additionally, ET-1 (100 nM) significantly potentiated the transient component (I KT) of the potassium currents. ET-1-induced effects were largely attenuated by BQ-788, a selective ETBR blocker. However, a selective ETAR blocker BQ-123 did not alter the effects of ET-1. A selective ETBR agonist, IRL-1620, mimicked the effect of ET-1 on I Na in a concentration-dependent manner (IC50 159.5 ± 92.6 µM). In conclusion, our results demonstrate that ET-1 hyperpolarizes nociceptors by blocking I Na and potentiating I KT through selective activation of ETBR, which may represent one of the underlying mechanisms for reported anti-nociceptive effects of ET-1.

11,12 -Epoxyeicosatrienoic acid (11,12 EET) reduces excitability and excitatory transmission in the hippocampus.

Recent studies suggest a role for the arachidonic acid-derived epoxyeicosatrienoic acids (EETs) in attenuating epileptic seizures. However, their effect on neurotransmission has never been investigated in detail. Here, we studied how 11,12- and 14,15 EET affect excitability and excitatory neurotransmission in mouse hippocampus. 11,12 EET (2 µM), but not 14,15 EET (2 µM), induced the opening of a hyperpolarizing K+ conductance in CA1 pyramidal cells. This action could be blocked by BaCl2, the G protein blocker GDPß-S and the GIRK1/4 blocker tertiapin Q and the channel was thus identified as a GIRK channel. The 11,12 EET-mediated opening of this channel significantly reduced excitability of CA1 pyramidal cells, which could not be blocked by the functional antagonist EEZE (10 µM). Furthermore, both 11,12 EET and 14,15 EET reduced glutamate release on CA1 pyramidal cells with 14,15 EET being the less potent regioisomer. In CA1 pyramidal cells, 11,12 EET reduced the amplitude of excitatory postsynaptic currents (EPSCs) by 20% and the slope of field excitatory postsynaptic potentials (fEPSPs) by 50%, presumably via a presynaptic mechanism. EEZE increased both EPSC amplitude and fEPSP slope by 40%, also via a presynaptic mechanism, but failed to block 11,12 EET-mediated reduction of EPSCs and fEPSPs. This strongly suggests the existence of distinct targets for 11,12 EET and EEZE in neurons. In summary, 11,12 EET substantially reduced excitation in CA1 pyramidal cells by inhibiting the release of glutamate and opening a GIRK channel. These findings might explain the therapeutic potential of EETs in reducing epileptiform activity.