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Current Trends in Biotechnology and PharmacyVol. 5 (2) 1193-1205 April 2011. ISSN 0973-8916 (Print), 2230-7303 (Online)1201A generalised reduction in brain cholinergicfunction has been reported in Pb-treated rats.Exposure to Pb resulted in a decrease in the AChEactivity in cerebellum and hippocampus at variouspost natal time points (22). Neonatal exposure toPb altered the muscarinic receptor density (27)which account for the deficits in central cholinergicfunctions (28). The results of our present studyare in agreement with these findings.The alterations in AChE activity duringearly postnatal development could be related withthe fact that Pb crosses the blood brain barrierquite readily (29). The inhibitory effect of Pb onAChE activity also reflected in alterations in themotor activity (30, 5). The results of the presentstudy showed maximum alterations in AChEcontent in hippocampus of Pb-treated rats. Thecholinergic synapses are more in hippocampusas compared to cerebral cortex and cerebellum(31). AChE inhibition in this area leads tocognitive and non cognitive alterations as this isthe principle area for memory and cognition. Thefact that the hippocampus develops late (32) andsequester, Pb, primarily in the mossy fibrepathway (33) would put this structure at particularrisk for damage following early Pb-exposure.Since the cholinergic system isresponsible for the behavioral manifestations, anyalteration in the cholinergic system would bereflected in the behavior. In the present study,the observed alterations in cholinergic systemhave greatly influenced the open field behaviorof rats exposed to Mn and Pb. The memory andspatial discrimination tasks in Morris water mazealso decreased suggesting the hippocampaldamage due to Pb+Mn exposure.Supplementation with Ca 2+ reversed the Pband Mn induced inhibition in AChE activity. Thereversal of inhibition in the activity of AChE bysupplementation with Ca 2+ may be due tocompetition of these metals for similar bindingsites and reducing the availability of binding sitesfor Pb or Mn.Ca 2+ is a divalent cation just like Pb.Because the same transport mechanism isoperative for absorption of Pb and Ca 2+ from thegastrointestinal tract there is resulting competitiveinteraction between Pb and Ca 2+ (34). Studieshave shown that Pb has an inhibitory effect onthe peripheral nervous system through stimuluscoupled or Ca 2+ dependent release ofacetylcholine (35) and this inhibitory effect of Pbat the neuromuscular junction and the ganglionwas similar to the effect of reducing theconcentration of Ca 2+ in bathing media of neuralpreparations; so it is not surprising that thisinhibitory effect of Pb can be overcome by theaddition of Ca 2+ . Absorption of Pb bygastrointestinal tract is inversely related to theamount of Ca 2+ present (36, 37). FurthermoreCa 2+ supplements had a protective effect bysignificantly reducing blood Pb levels in pregnantwomen whose diets were deficient in Ca 2+ (38,39). Ziegler et al., (40) observed an inverserelationship between dietary Ca 2+ and Pbretention and absorption in young infants.Pb+Mn-exposure exerted inhibitoryaction on the activity of enzymes Mg 2+ , andNa + K + ATPases in the developing brain. Heavymetals such as Pb can bind to a number of siteson proteins including imidazole, histodyl, carbonyland especially sulfhydryl side chains (41). Heavymetals have great affinity for ATPase system andthey interact with enzyme molecule resulting inthe inhibition (42). Pb has been reported to inhibitNa + K + ATPase of mammalian tissues (43, 44) andalso interferes with mitochondrial function andblocks the O 2uptake. Bhaumik and Raychudhari(45) reported that the inhibition of Na + K + ATPasemay be due to the flow of the Na + K + ions fromthe tissues to the blood. The decrease in theMg 2+ ATPase activity might be due to lowoperation of oxidative pathway, resulting inCalcium protection against lead and manganese toxicity
Current Trends in Biotechnology and PharmacyVol. 5 (2) 1193-1205 April 2011. ISSN 0973-8916 (Print), 2230-7303 (Online)1202decreased formation of free energy and alteredcellular energy metabolism (46).The combination of Pb 2+ and Mn 2+produced a pronounced decrease in the activityof Na + K + -ATPase, but the magnitude of thechange was the sum of the individual metaleffects. (47). It is known that brain derivedNa + K + ATPase is among the enzymes particularlyaffected by Pb (48-50). The decrease ofNa + K + ATPase activity can change the gradientsof Na + and K + across the cell membrane and canbe the cause of the disturbances inneurotransmitters levels (50).The observed high activity of ATPase inthe cortex, cerebellum and hippocampus regionsof the brain suggests the involvement of theseregions in different behavioral functions. It isknown that the level of ATPase parallels themetabolic demands of different regions of rat brainand the differential sensitivity to Pb+Mnneurotoxicity in these brain regions is not due to apreferential metal accumulation, but is possiblydue to alteration of biochemical or cellularprocesses that are uniquely associated with, orgreatly enhanced in a particular region (51, 8).Regional variations in AChE and ATPases activitylevels observed in different brain regions couldbe due to structural and functional differences inbrain regions. Addition of Ca 2+ reduced theeffects of Pb+Mn on the activities of AChE andATPases in brain regions. The supplemented Ca 2+may compete for similar binding sites as that ofPb and Mn. Supplementation with Ca 2+ decreasesPb gastrointestinal absorption and decreasestissue accumulation (52). Thus Ca 2+ replaces Pband Mn in the body reducing the Pb+Mn-burdenin the body.Thus, from the present study, it is evidentthat exposure to a combination of Pb and Mninhibited the activities of both Mg 2+ ATPase andNa + K + ATPase enzymes as well as AChE leadingto decrease in motor and cognitive functions.Calcium supplementation significantly reversedthese alterations in enzyme activities as well asbehavioral functions suggesting therapeutic roleof calcium for Pb+Mn induced neurotoxicity.AcknowledgementsThe authors acknowledge the financialsupport from CSIR Grant No. 37(1349)/08/EMR-II and DST Grant No.SR/SO/AS-72/2008.References1. Kuhlmann, A.C., Mc Glothan, J. L. andGuilarte, T. R. (1997). Developmental leadexposure causes spatial learning deficits inadult rats. Neurosci. Lett. 233: 101-104.2. Zawia, N. H., Sharan, R., Brydie, M.,Uyama, T. and Crumpton, T. (1998). SP1as a target site for metal-inducedperturbations of transcriptional regulation ofdevelopmental brain gene expression. Dev.Brain Res. 107: 291-298.3. Reddy, G. R. and Zawia, N. H. (2000). Leadexposure alters Egr-1 DNA binding in theneonatal rat brain. Int. J. Dev. Neurosci.18: 791-795.4. Chetty, C. S., Reddy, G. R., Murthy, K. S.,Johnson, J., Sajwan K. and Desaiah D.(2001). Prenatal lead exposure alters theexpression of neuronal nitric oxide synthasein rat brain. Int. J. Toxicol. 20: 113-120.5. Basha, M. R., Wei, W., Brydie, M.,Razmiafshari M. and Zawia, N. H. (2003).Lead induced developmental perturbationsin hippocampal Sp1 DNA-binding areprevented by zinc supplementation. Int. J.Dev. Neurosci. 21: 1-12.6. Devi, C. B., Reddy, G. H., Prasanthi, R. P.J., Chetty, C. S. and Reddy, G. R. (2005).Developmental lead exposure altersmitochondrial monoamine oxidase andRam Kumar et al
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