2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Chronic-Disease

A large body of evidence has suggested that the disruptions of neural plasticity in the brain play a pivotal role in major depressive disorder (MDD). Electroacupuncture (EA) therapy has been shown to be an effective treatment modality for MDD. However, the mechanism underling the antidepressive effect of EA treatment has not been clearly elucidated. This study aimed to investigate the antidepressant-like effects of EA associated with its protection effect of synaptic structural plasticity.. An MDD model was induced by exposing Sprague Dawley rats to chronic unpredictable mild stress (CUMS). EA stimulation (Hegu and Taichong) and AMPA receptor (AMPAR) antagonist NBQX intrahippocampal injection were used to treat the depressed rats.. We found EA improved behavioral performance, enhanced synaptic structural plasticity, and upregulated gene and protein levels of GluR1, GluR2, Stargazin, Pick1, SYP, PSD-95, and GAP-43. AMPAR antagonist NBQX had the opposite effect on behavioral performance, synaptic plasticity, and the aforementioned genes and proteins.. These results suggest that EA has a potent antidepressant effect, likely through upregulated expression of the AMPAR and protected neural plasticity in CUMS-treated rats.

Topics: Animals; Behavior, Animal; Chronic Disease; Depression; Electroacupuncture; Excitatory Amino Acid Antagonists; Hippocampus; Male; Neuronal Plasticity; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Stress, Psychological; Synapses

The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.

Topics: Animals; Anticonvulsants; Chronic Disease; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Female; Hippocampus; Kainic Acid; Mice; Nitriles; Phenytoin; Pyridones; Quinoxalines; Receptors, AMPA; Seizures; Status Epilepticus

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.

Topics: Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hyperalgesia; Injections, Spinal; Male; Motor Activity; Pain; Physical Stimulation; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Injuries; Valine

Two patterns of transforming growth factor-beta1 (TGF-beta1) expression were identified in brains of normotensive rats following permanent occlusion of the middle cerebral artery (MCAO). First, a relative increase of TGF-beta1 mRNA by 37% was found at 12 h after MCAO in the ipsilateral cingulate cortex as compared to the homotopic contralateral region. The cingulate cortex is located distant from the ischemic territory. Treatment with the glutamate receptor antagonists MK-801 and NBQX did not reduce this expression (34% and 26% increase, respectively). Therefore, peri-infarct depolarization waves were probably not responsible for induction. Secondly, an increase of TGF-beta1 mRNA by 116% was found at 7 days after MCAO within infarcted tissue. This expression was not reduced by the glutamate receptor antagonists MK-801 (increase 140%) and NBQX (increase 137%), either. TGF-beta1 mRNA expression in the cingulate cortex at 12 h after MCAO is possibly mediated by neurons and astroglia and may support cell survival. Expression in the infarcted tissue at 7 days after MCAO is most likely related to the invasion of monocytes and may be involved in the downregulation of inflammatory events, in neoangiogenesis, and in formation of a glial scar around the infarct.

Topics: Animals; Arterial Occlusive Diseases; Brain; Cerebral Arteries; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Quinoxalines; Rats; Rats, Inbred F344; RNA, Messenger; Transforming Growth Factor beta

A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemically administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury.

Topics: Animals; Behavior, Animal; Chronic Disease; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Ischemia; Motor Activity; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries