Clioquinol, And Vitamin B12 Synaptic Plasticity Damage Caused By Chronic Lead Collaborative Repair

Lead (Pb²⁺) is one of the most important neurotoxic metals in the environment. It has now well established that the chronic Pb²⁺ exposure in development produces deficits of learning and memory, cognitive deficits and neurobehavioral dysfunction in children and in a lot of animal species. Hippocampus is a region related to learning and memory. The activity-dependent synaptic plasticity is regarded as the electrophysiological substrate for learning and memory. Pb²⁺ exposure in development induces impairments of synaptic plasticity in hippocampus of rats, which possibly contribute to deficits of learning and memory, cognitive deficits and neurobehavioral dysfunction by chronic Pb²⁺ exposure.At present, chelation therapy is popular for treating lead-induced neurotoxicity. But the common chelating agents have many adverse effects and are incapable of alleviating lead-induced neurotoxicity. Recently, clioquinol(CQ), which is a transition metal ion chelator and /or ionophore with low affinity for metal ions, has yielded some promising results in animal models and clinical trials related to dysfunctions of metal ions, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). In the 1970s, CQ was banned in many countries due to being linked to outbreak of subacute myelo-optic neuropathy (SMON) in Japan. However, now CQ-associated side effects are believed to be overcome with VB12 supplementation.To determine whether CQ treatment could rescue impairments of synaptic plasticity induced by chronic Pb²⁺ exposure, we investigated the input/output functions (I/O), paired-pulse reactions (PPR) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anaesthetized rat in vivo by recording field potentials and measured hippocampal Pb²⁺ concentrations of different treatment groups by PlasmaQuad 3 inductive coupled plasma mass spectroscopy in this paper. The main results were summarized as followings:1. CQ alone does not rescue the lead-induced impairments of synaptic plasticity in hippocampal DG area of the anaesthetized rats in vivo. In controls, the average peak facilitation was 225±17% at IPI=60 ms and the LTP amplitude was 136±4 % (fEPSP slope) and 266±17 % (PS amplitude); in lead-exposed group, the average peak facilitation was 180±12.5% at IPI=60 ms and the LTP amplitude was 122±2% (fEPSP slope) and 195±10.4% (PS amplitude); in lead+CQ group, the average peak facilitation was 180±24.3% at IPI=60 ms and the LTP amplitude was 125±3.4% (fEPSP slope) and 199±14.7% (PS amplitude). The corresponding data by analysis indicate that chronic Pb²⁺ exposure induces impairments of PPR and LTP in hippocampal DG area of the anaesthetized rats in vivo however, CQ alone does not rescue these impairments.Pb²⁺ could bind to many macromolecules in organisms by mimicking calcium (Ca²⁺) to form metalloprotein compounds, which possibly resulted in the corruption of an antioxidant metalloprotein system and mediated the lead-induced impairments. CQ could serve as a metal-protein-attenuating compound (MPAC) by interacting with metalloprotein systems. The benefits of CQ seemed to be due to its ability to bind to the lead-protein complex to attenuate the internal interaction of complex. However, the decreased amounts of VB12 in the brain and blood of mice that had been administered CQ has been reported. The VB12 deficiency was suspected to be related to SMON, a probably adverse effect of CQ. The reason why CQ treatment alone does not rescue these impairments maybe is due to the VB12 deficiency caused by CQ administration, which antagonizes beneficial results of CQ administration.2. VB12 alone partly rescues the lead-induced impairments of LTP.In lead+VB12 group, the average peak facilitation was 178±19.4% at IPI=60 ms and the LTP amplitude was 126±3.6% (fEPSP slope) and 226±15.7% (PS amplitude). Combined with corresponding data of controls and lead-exposed group, the results indicate that VB12 alone partly rescues impairments of PPR and LTP in hippocampal DG area of the anaesthetized rats in vivo.Chronic Pb²⁺ exposure produced impairments partly by oxidative stress of Pb²⁺. One possible molecular mechanism involved in the Pb²⁺ neurotoxicity is the disruption of the prooxidant/antioxidant balance. VB12 supplementation possibly rebalances the prooxidant/antioxidant ratio, which contribute to the main reason why VB12 administration partly rescues the lead-induced impairments of LTP.3. The co-administration of CQ and VB12 synergistically rescues these impairments of synaptic plasticity and moreover, the effects of CQ and VB12 co-administration are specific to the lead-exposed animals.In lead+CQ+VB12 group, the average peak facilitation was 216±19.3% at IPI=60 ms and the LTP amplitude was 138±2.8% (fEPSP slope) and 273±18.1% (PS amplitude). Combined with corresponding data of controls and lead-exposed group, the results indicate that co-administration of CQ and VB12 synergistically, almost totally, rescues impairments of PPR and LTP in hippocampal DG area of the anaesthetized rats in vivo.Under condition of the CQ and VB12 co-administration, not only can CQ redress the dysfunctions of metalloprotein systems produced by chronic Pb²⁺ exposure and decrease oxidative stress induced by chronic Pb²⁺ exposure, but also VB12 administration can counteract the VB12 deficiency caused by CQ administration. So, CQ and VB12 show synergistic effects on repairing the lead-induced impairments of synaptic plasticity and they almost totally rescue these impairments in hippocampal DG area of the anaesthetized rats in vivo. Moreover, co-administration of CQ and VB12 dose not make improvements of synaptic plasticity in controls, indicating that synergistic effects are specific to lead-exposed group. In addition, data of hippocampal Pb²⁺ levels in different groups indicate that these synergistic effects are not independent of elimination of Pb²⁺ from brain tissue by CQ and/or VB12.