Ischemia-induced Depression Research Articles

Global Cerebral Ischemia-induced Depression Accompanies Alteration of Neuronal Excitability in the Infralimbic Cortex Layer 2/3 Pyramidal Neurons.

Cerebral ischemia can lead to a range of sequelae, including depression. The pathogenesis of depression involves neuronal change of the medial prefrontal cortex (mPFC). However, how cerebral ischemia-induced changes manifest across subregions and layers of the mPFC is not well understood. In this study, we induced cerebral ischemia in mice via transient bilateral common carotid artery occlusion (tBCCAO) and observed depressive-like behavior. Using whole-cell patch clamp recording, we identified changes in the excitability of pyramidal neurons in the prelimbic cortex (PL) and infralimbic cortex (IL), the subregions of mPFC. Compared to sham control mice, tBCCAO mice showed significantly reduced neuronal excitability in IL layer 2/3 but not layer 5 pyramidal neurons, accompanied by increased rheobase current and decreased input resistance. In contrast, no changes were observed in the excitability of PL layer 2/3 and layer 5 pyramidal neurons. Our results provide a new direction for studying the pathogenesis of depression following ischemic damage by showing that cerebral ischemia induces subregion- and layer-specific changes in the mPFC pyramidal neurons.

Raised Intracellular Calcium Contributes to Ischemia-Induced Depression of Evoked Synaptic Transmission.

Oxygen-glucose deprivation (OGD) leads to depression of evoked synaptic transmission, for which the mechanisms remain unclear. We hypothesized that increased presynaptic [Ca2+]i during transient OGD contributes to the depression of evoked field excitatory postsynaptic potentials (fEPSPs). Additionally, we hypothesized that increased buffering of intracellular calcium would shorten electrophysiological recovery after transient ischemia. Mouse hippocampal slices were exposed to 2 to 8 min of OGD. fEPSPs evoked by Schaffer collateral stimulation were recorded in the stratum radiatum, and whole cell current or voltage clamp recordings were performed in CA1 neurons. Transient ischemia led to increased presynaptic [Ca2+]i, (shown by calcium imaging), increased spontaneous miniature EPSP/Cs, and depressed evoked fEPSPs, partially mediated by adenosine. Buffering of intracellular Ca2+ during OGD by membrane-permeant chelators (BAPTA-AM or EGTA-AM) partially prevented fEPSP depression and promoted faster electrophysiological recovery when the OGD challenge was stopped. The blocker of BK channels, charybdotoxin (ChTX), also prevented fEPSP depression, but did not accelerate post-ischemic recovery. These results suggest that OGD leads to elevated presynaptic [Ca2+]i, which reduces evoked transmitter release; this effect can be reversed by increased intracellular Ca2+ buffering which also speeds recovery.

3-Nitropropionic acid-induced depression of spinal reflexes involves mechanisms different from ischemia-induced depression

Effect of 3-nitropropionic acid (3-NPA) and ischemia (glucose- and O 2-free solution) on synaptic transmission in hemisected spinal cord from 4 to 8 day old rats was examined in vitro. Stimulation of a dorsal root (L3-5 segments) evoked monosynaptic (MSR) and polysynaptic reflex (PSR) potentials in the segmental ventral root. Superfusion of 3-NPA (0.17–3.4 mM) depressed the reflexes in a concentration- and time-dependent manner. At 3.4 mM of 3-NPA, the reflexes were abolished by 35 min. Time required to produce 50% depression (T-50) was around 170, 80, 40 and 17 min for MSR and 110, 70, 25 and 16 min for PSR at 0.17, 0.51, 1.7 and 3.4 mM of 3-NPA, respectively. Ischemia also produced a time-dependent depression of reflexes and abolished them by 35 min and the T-50 values were around 18 min. Presence of creatine phosphate (10 mM) in the superfusing medium did not alter the time course of 3-NPA-induced depression of reflexes but prolonged the ischemia-induced depression. dl-2-amino-5-phosphonovaleric acid (NMDA receptor antagonist; 10 μM) failed to block the 3-NPA (3.4 mM)-induced depression of reflexes, but blocked the ischemia-induced depression. The results indicate that 3-NPA-induced depression of spinal reflexes does not involve NMDA receptors and is different from ischemia-induced depression.

3-Nitropropionic acid-induced depression of spinal reflexes does not involve 5-hydroxytryptaminergic system in contrast to ischemia-induced depression in neonatal rat spinal cord in vitro

The involvement of 5-hydroxytryptaminergic (5-HTergic) system for the 3-nitropropionic acid (3-NPA)-induced depression of spinal reflexes was evaluated and compared with other energy deficiency condition (ischemia; glucose-free and O 2-free). The monosynaptic (MSR) and polysynaptic reflex (PSR) potentials were recorded at ventral root by stimulating the corresponding dorsal root in neonatal rat spinal cord in vitro. Superfusion of 3-NPA (3.4 mM) or ischemic solution depressed the reflexes in a time-dependent manner abolishing them by 35 min. Pretreatment with pindolol (1 μM), ketanserin (10 μM) or ondansetron (0.1 μM); 5-HT 1, 5-HT 2, or 5-HT 3 receptor antagonist, respectively, did not block the 3-NPA-induced depression of reflexes whereas, ischemia-induced depression was blocked by ondansetron. 5-HT content of the spinal cords incubated with 3-NPA (3.4 mM) for 30 min was decreased significantly (33 ng/g tissue) while increased (286 ng/g) in cords exposed to ischemic solution as compared to saline-treated cords (161 ng/g). Thus, 3-NPA-induced depression of spinal reflexes does not involve 5-HTergic pathway unlike ischemia-induced depression.

Ischemia-induced activation of AMPK does not increase glucose uptake in glycogen-replete isolated working rat hearts

Alterations in myocardial glucose metabolism are a key determinant of ischemia-induced depression of left ventricular mechanical function. Since myocardial glycogen is an important source of endogenous glucose, we compared the effects of ischemia on glucose uptake and utilization in isolated working rat hearts in which glycogen content was either replete (G replete, 114 micromol/g dry wt) or partially depleted (G depleted, 71 mumol/g dry wt). The effects of low-flow ischemia (LFI, 0.5 ml/min) on glucose uptake, glycogen turnover (glycogenolysis and glycogen synthesis), glycolysis, adenosine 5'-monophosphate-activated protein kinase (AMPK) activity, and GLUT4 translocation were measured. Relative to preischemic values, LFI caused a time-dependent reduction in glycogen content in both G-replete and G-depleted groups due to an acceleration of glycogenolysis (by 12-fold and 6-fold, respectively). In G-replete hearts, LFI (15 min) decreased glucose uptake (by 59%) and did not affect GLUT4 translocation. In G-depleted hearts, LFI also decreased initially glucose uptake (by 90%) and glycogen synthesis, but after 15 min, when glycogenolysis slowed due to exhaustion of glycogen content, glucose uptake increased (by 31%) in association with an increase in GLUT4 translocation. After 60 min of LFI, glucose uptake, glycogenolysis, and glycolysis recovered to near-preischemic values in both groups. LFI increased AMPK activity in a time-dependent manner in both groups (by 6-fold and 4-fold, respectively). Thus, when glycogen stores are replete before ischemia, ischemia-induced AMPK activation is not sufficient to increase glucose uptake. Under these conditions, an acceleration of glycogen degradation provides sufficient endogenous substrate for glycolysis during ischemia.

Aglycemia and ischemia depress monosynaptic and polysynaptic reflexes in neonatal rat spinal cord in vitro by involving different types of 5-hydroxytryptamine receptors

Involvement of 5-hydroxytryptaminergic (5-HT) system for aglycemia- and ischemia-induced depression of the spinal reflexes was evaluated. The monosynaptic (MSR) and polysynaptic (PSR) reflex potentials were elicited in the ventral root by stimulating the corresponding dorsal root in an isolated spinal cord from neonatal rat. Superfusion of aglycemic (glucose-free) or ischemic (glucose- and O 2-free) solution produced a time-dependent depression of the spinal reflexes and abolished them within 35 min. The time required to produce 50% depression of the reflexes (T-50) was around 19 and 13 min for aglycemia and ischemia, respectively. Spiperone (5-HT 2A antagonist) and ketanserin, (5-HT 2A/2C antagonist) blocked the aglycemia-induced depression of the reflexes completely while ondansetron (5-HT 3 antagonist) attenuated it partially (as abolition times were around 50 min). Ischemia-induced depression was blocked up to 50 min by ketanserin or ondansetron but not by spiperone. In the presence of ketanserin or ondansetron, the reflexes were abolished by 60 min while in spiperone the reflexes were abolished by 30 min. In 5,7-dihydroxytryptamine treated rats, aglycemia depressed the reflexes by 45 min (greater than control, P < 0.05) while the time for ischemia-induced depression was not different from the control response. The results indicate that aglycemia involves mainly 5-HT 2 receptors while ischemia involves 5-HT 3 receptors.

Deprenyl blocks the aglycemia-induced depression of the synaptic transmission but not the ischemia-induced depression in neonatal rat spinal cord in vitro

The protective action of R-(−)-deprenyl against the aglycemia (glucose-free) and the ischemia (glucose-free and O 2-free)-induced changes in the synaptic transmission was investigated. The in vitro “glucose-free and O 2-free” condition mimics in vivo ischemia where there is a deficiency of O 2 and energy substrate, hence the term ischemia was used. The monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials were elicited in the ventral root by stimulating the corresponding dorsal root in an isolated spinal cord from the neonatal rat. Aglycemia and ischemia depressed the spinal reflexes in a time-dependent manner and abolished them within 30 min. The 50% depression of the reflexes (T-50) occurred around 25 min for aglycemia and 15 min for ischemia. Creatine phosphate, an energy supplement, attenuated the aglycemia- and ischemia-induced depression of the reflexes. The T-50 values for both the reflexes were around 40 and 25 min for aglycemia and ischemia, respectively. Deprenyl (10 μM) blocked the aglycemia-induced depression completely but failed to block the ischemia-induced depression. The present results indicate that aglycemia and ischemia abolished the synaptic transmission simultaneously and energy supplementation partially attenuated the depression. The protective effects of deprenyl against aglycemia may not be due to its MAO-B action and suggest for the involvement of non-MAO-B mechanisms.

Effects of hemodynamic variables on myocardial K + balance during and after shortlasting ischemia

Ischemia-induced myocardial potassium loss and post-ischemic potassium reuptake was quantitated in 8 open chest pigs during control conditions and during hemodynamic alterations which have been shown to increase steady state sarcolemmal potassium fluxes. Myocardial K + balance was continuously computed before, during and after a 90 s occlusion of a branch of the circumflex artery during control (CTR), during pacing tachycardia (PACE: 34% increase in heart rate), during proximal aortic constriction (AC; 28% increase in LVSP), and during isoprenaline infusion (ISO; 135% increase in LVdP dt and 35% increase in heart rate). Ischemia-induced potassium loss increased significantly (40%) during ISO only. Higher basal metabolic rate, increased sarcolemmal K + conductance, or ischemia-induced depression of a more active Na K -pump during ISO are possible explanations to why increased K + loss appeared in this situation. The maximal rate of post-ischemic potassium reuptake was not different from CTR during PACE and ISO, but it was reduced during AC, which might be due to persisting subendocardial ischemia in early reperfusion when ventricular wall stress is high. The extent of potassium restoration was not different from CTR during AC, PACE and ISO.