Pharmacologic Treatment with GABAB Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice

Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABAB receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABAA receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABAB receptors may constitute a putative new target in treating cognitive deficits in chronic METH users

Matrix Metalloproteinases Contribute to Neuronal Dysfunction in Animal Models of Drug Dependence, Alzheimer's Disease, and Epilepsy

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy

可塑的脳機能変化における組織プラスミノーゲン活性化因子の役割

金沢大学医薬保健研究域薬学系神経伝達物質ドパミンの遊離調節における組織プラスミノーゲン活性化因子(tPA)-プラスミン系プロテアーゼシグナルの役割について検討するために、tPA-プラスミン系シグナル関連分子をマウスの側坐核に微量注入し、高カリウム刺激、モルヒネおよびニコチン誘発性ドパミン遊離の変化をin vivo brain dialysis法を用いて解析した。1.tPA-プラスミン系シグナルを抑制するプラスミノーゲン活性化因子抑制因子(PAI-1)は、高カリウム刺激、モルヒネおよびニコチン誘発性ドパミン遊離を濃度依存的に抑制した。2.tPA-プラスミン系シグナルを活性化するtPAおよびプラスミンは、高カリウム刺激、モルヒネおよびニコチン誘発性ドパミン遊離を濃度依存的に増強した。3.tPA遺伝子欠損(tPA-KO)マウスでは、野生型マウスに比較して、高カリウム刺激、モルヒネおよびニコチン誘発ドパミン遊離が著明に減弱していた。4.tPA-KOマウスにおける上記のドパミン遊離の障害は、側坐核にtPAあるいはプラスミンを微量注入することにより、ほぼ完全に回復した。5.野生型マウスの両側の側坐核にtPAを微量注入すると、モルヒネにより誘発される運動量の増加が著明に増強された。6.野生型マウスの両側の側坐核にPAI-1を微量注入すると、モルヒネにより誘発される運動量の増加が著明に抑制された。以上の結果より、tPA-プラスミン系プロテアーゼシグナルは側坐核におけるドパミン遊離の制御に重要な役割を果たしており、プラスミンはドパミン遊離を促進的に調節していることが示唆された。研究課題/領域番号:14658249, 研究期間(年度):2002 – 2003出典：「可塑的脳機能変化における組織プラスミノーゲン活性化因子の役割」研究成果報告書　課題番号14658249（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14658249/)を加工して作

Matrix metalloproteinases contribute to neuronal dysfunction in animal models of drug dependence, Alzheimer’s disease

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy

The Latent Risk of Acidosis in Commercially Available Total Parenteral Nutrition (TPN) Products: a Randomized Clinical Trial in Postoperative Patients

To evaluate the latent risk of acidosis in commercially available total parenteral nutrition (TPN) products, three types of commercially available TPN products were compared in postoperative patients. Sixty-four hospitalized patients with gastro-intestinal disease who undertook curative gastro intestinal resection were studied prospectively and administered with TPN solutions. Three types of commercially available TPN products were assigned randomly to eligible patients. Serial studies of blood acid-base status, serum electrolytes, and urinary acid-base status were conducted in the three groups administered with different TPN solutions. Patients received appropriate electrolytic solutions on the operation day and TPN solution from 2 to 7 days after operation. There were no differences among any of the serum electrolytes in the three groups. In one group, urinary pH decreased slightly and urinary net acid excretion (NAE) increased significantly after administration. This TPN product contains about 40 mEq/L of non-metabolizable acid to avoid the Maillard reaction that produces a complex of glucose and amino acids. Urinary NAE did not change in the other two groups. These TPN products do not use non-metabolizable acid to adjust pH. The present results suggest that the non-metabolizable acid may be a risk factor of metabolic acidosis

Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow‐Altered Carotid Arteries of Apolipoprotein E Knock‐Out Mice

[Background] Chronic inflammation through cellular senescence, known as the senescence‐associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long‐term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation‐induced atherosclerosis and senescence‐associated secretory phenotype in murine carotid arteries. [Methods and Results] Partial ligation of the left carotid artery branches in 9‐week‐old male apolipoprotein E‐deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin‐dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein‐1, keratinocyte‐derived chemokine, and macrophage inflammatory protein 2). [Conclusions] IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence‐associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation‐induced atherosclerosis