PMC:4277126 / 119382-134691 JSONTXT

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There is increased interest in seeking new therapeutic agents for these devastating diseases from herbal medicines. LBPs possess neuroprotective effects in various in vitro and in vivo models152–154 but the mechanisms have not yet been fully elucidated. In the nervous system, LBPs can protect against neuronal injury or loss induced by I/R,155,156 Aβ peptide,157,158 glutamate excitotoxicity, and other neurotoxic insults.154 LBPs also enhance neurogenesis.154,159\n\nIschemic brain disease and MCAO\nIschemic stroke has become one of the most devastating diseases, which cause high rates of disability and mortality in aged people.160–162 Acute excitotoxicity, oxidative stress, and inflammation are the three primary mechanisms involved in cell death during ischemic stroke.163 Cerebral edema is a detrimental feature after ischemic stroke and is one of the impact factors of clinical deterioration within the first 24 hours after stroke onset. Cerebral ischemia and reperfusion triggers a cascade of cellular events including cell death, oxidative stress, and inflammation, which all contribute to the breakdown of blood–brain barrier (BBB).160–162 Neuronal cell apoptosis plays an important role in the development of ischemic injury in the brain tissue. Mitochondrial apoptotic pathway is a major apoptotic pathway, and a large number of apoptosis-related proteins in mitochondria play an important role in the initiation and development of neuronal apoptosis.164 Pro-apoptotic and anti-apoptotic Bcl-2 family proteins play important roles in mitochondrial apoptotic pathway. Bax is a pro-apoptotic and Bcl-2 is an anti-apoptotic protein in the Bcl-2 family. Cytochrome C binds and activates apoptotic protease-activating factor-1 as well as procaspase-9, forming an apoptosome together with ATP. Apoptosome then activates caspase-9, leading to caspase-3 activation and eventually cellular apoptosis. Caspase-3 has been identified as a key mediator of apoptosis and cleaves the substrate PARP-1, which is a multifunctional nuclear enzyme whose activity is rapidly stimulated by DNA breaks.\nThe protective effect of LBPs was investigated in primary cultured rat hippocampal neurons subject to oxygen–glucose deprivation/reperfusion by Rui et al.153 Cultured hippocampal neurons were exposed to oxygen–glucose deprivation for 2 hours followed by a 24-hour re-oxygenation. Treatment with LBPs (10–40 mg/L) significantly attenuated neuronal damage and inhibited LDH release in a dose-dependent manner.153\nYang et al155 investigated the protective effect of LBP pre-treatment in an experimental stroke (MCAO) model in male C57BL/6N mice. To gain LBPs, dry L. barbarum residues were dissolved in water at 70°C, and the supernatant was concentrated, precipitated with 95% ethanol, and then vacuum dried to produce the extracts. The mice were administered 1 mg/kg or 10 mg/kg LBPs daily for 7 days, and then subjected to 2-hour transient MCAO by the intraluminal method followed by 22-hour reperfusion upon filament removal. LBP pre-treatment dose-dependently improved neurological deficits; decreased infarct size, apoptotic neurons in ischemic penumbra area, and cerebral edema; and protected the brain from BBB disruption as indicated by reduced Evans Blue dye leakage into the ipsilateral hemispheres and an upregulation of occludin expression.155 Occludin, one of the proteins located at tight junctions, plays an important role in maintaining the integrity of BBB. Pre-treatment with 10 mg/kg LBPs for 7 days also profoundly suppressed the upregulation of AQP4 expression in ipsi-lateral penumbral areas.155 Furthermore, 10 mg/kg LBPs suppressed GFAP activation in ipsilateral penumbral areas. Pre-treatment with 10 mg/kg LBPs reduced both nitrosative stress and lipid peroxidation in cerebral ischemic penumbra after MCAO. LBPs at both doses attenuated the expression of matrix metalloproteinase-9 (MMP-9) in ipsilateral penumbral areas.155 These findings clearly demonstrate the beneficial prophylactic effects of LBPs against ischemic damage and cerebral edema in a murine experimental stroke model. The neuroprotective effects of LBPs on ischemic stroke include reduction of neuronal damage and infarct, maintenance of BBB integrity, and alleviation of cerebral edema through antioxidation, suppression of upregulated MMP-9 and AQP4, anti-apoptosis, and inhibition of glial activation.\nIn a study using male Kunming mice, Wang et al165 examined the effect of intragastric administration with LBPs on brain injuries in MCAO mice. The study demonstrated that LBPs at doses of 20 mg/kg and 40 mg/kg significantly decreased the neurological deficit scores and the infarct area in MCAO mice. LBPs also significantly decreased MDA content, and increased SOD, GPx, CAT, and LDH activities in the ischemic brain.165 These findings suggest that LBPs might act as potential neuroprotective agent against the cerebral reperfusion-induced brain injury through reducing lipid peroxides, scavenging free radicals, and improving the energy metabolism.\nIn a similar study, Wang et al156 used male Imprinting Control Region mice to make the model of MCAO and investigated the protective effect of intragastric administration of 10 mg/kg, 20 mg/kg, and 40 mg/kg body weight LBPs or 0.4 mg/kg nimodipine for 7 days on MCAO-induced brain injuries. The results showed that intragastric administration of 20 mg/kg and 40 mg/kg LBPs markedly decreased the neurological deficit scores and the infarct volume in MCAO mice.156 Administration of 10–40 mg/kg LBPs also reduced neuronal morphological damage and neuronal apoptosis in ischemic penumbra of the left cortex. About 40 mg/kg LBPs significantly suppressed cortex overexpression of Bax, cytochrome C, caspase-3, -9, and cleaved PARP-1, and reduced the downregulated Bcl-2 expression in MCAO mice.156\nIn summary, the protective effects of LBPs on MCAO-induced brain injuries are mainly attributed to the reduction of oxidative stress, inhibition of apoptosis, and increase in the integrity of BBB. LBPs treatment reduces the oxidative stress via increasing the SOD, GPx, CAT, and LDH activities, but decreasing the content of MDA and lipid peroxidation. LBPs also inhibit the apoptosis via decreasing the expression of cytochrome C, cleave caspase-9, caspase-3, Bax, and cleaved PARP-1, but increasing the expression level of Bcl-2. In addition, LBPs increase the integrity of BBB expression through the upregulation of expression of occludin, but downregulation of the expression of MMP-9 and AQP4 (Figure 10).\n\nAβ-induced neuronal injury and AD\nAβ peptides are thought to be associated with the progressive neuronal death observed in AD. The effect of LBPs was investigated by Yu et al157 on the neuronal injury induced by Aβ1-42 and Aβ25-35 peptides in primary rat cortical neurons. Remarkable apoptosis and necrosis in primary rat cortical neurons were observed when exposed to Aβ peptides. Pre-treatment with LBPs significantly reduced the release of LDH. In addition, LBPs attenuated Aβ peptide-activated caspase-3-like activity.157 Aβ peptides induce a rapid activation of c-JNK by phosphorylation. Pre-treatment of LBPs markedly reduced the phosphorylation of JNK-1 at Thr183/Tyr185 and its substrates c-Jun-I at Ser73 and c-Jun-II at Ser63.157 LPBs elicit dose-dependent neuroprotective effects via regulation of JNK-1 pathway.\nYu et al158 also investigated the effects of LBPs on the phosphorylation of the double-stranded RNA-dependent protein kinase (PKR) in rat cortical neurons exposed to Aβ peptides. PKR is an intracellular sensor of stress and can arrest protein synthesis by phosphorylating the alpha subunit of the translation initiation factor eIF2. Pretreatment of LBPs effectively protected neurons against Aβ-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. LBPs markedly reduced Aβ-induced PKR phosphorylation.158\nIn summary, LBPs protect neurons against Aβ-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9 (Figure 11). LBPs inhibit the phosphorylation of JNK-1 at Thr183/Tyr185 and its substrates c-Jun-I at Ser73 and c-Jun-II at Ser63 in neurons. LBPs reduce the phosphorylation of Erk1/2m but not GSK3β. LBPs also markedly reduced Aβ-induced PKR phosphorylation. LBPs also significantly reduce homocysteine-induced phosphorylation of Tau-1 at Ser198/199/202, pS396 at Ser396, and pS214 at Ser214 as well as cleavage of Tau.\n\nScopolamine-induced brain injury\nA recent study by Chen et al154 reported the therapeutic effects of LBPs on learning and memory and neurogenesis in scopolamine (SCO)-treated adult male Sprague–Dawley rats. SCO was used to induce learning and memory deficits. LBPs were administered 0.2 mg/kg or 1 mg/kg body weight per day via gastric perfusion for 14 days before the onset of subcutaneous SCO treatment for a further 4 weeks. LBPs used were extracted with boiling water, followed by precipitation with ethanol, protein hydrolysis, dialysis, and fractionation with a diethylaminoethanol-Sepharose CL-6B column. An osmotic pump containing SCO solution at 440 mg/mL was subcutaneously embedded in the abdominal wall of rats and SCO release at a rate of 0.25 µL/h was maintained for 28 days and administration of LBPs was continued as before, throughout SCO treatment. LBPs at both doses almost restored the memory and learning abilities in SCO-treated rats.154 LBPs prevented SCO-induced reduction in neuronal proliferation and enhanced neuroblast differentiation in the hippocampal dentate gyrus of rats.\nLBP treatment also protected the dendrites from damage by SCO. LBPs dose-dependently decreased the SCO-induced oxidative stress in hippocampus and reversed the increased ratio of Bax/Bcl-2 induced by SCO treatment.154 LBPs significantly increased hippocampal SOD and GPx activity and reduced MDA level in SCO-treated rats. However, LBPs did not affect the SCO-induced elevation of hippocampal acetylcholinesterase activity and decrease of brain-derived neurotrophic factor level.154 These results suggest that LBPs prevent SCO-induced cognitive and memory impairments and reductions in hippocampal cell proliferation and neuroblast differentiation. Anti-oxidation and anti-apoptosis are the two major mechanisms for the neuroprotective effects of LBPs in SCO-treated rats (Figure 12).\n\nGlutamate-induced neuronal injury\nGlutamate excitotoxicity is involved in many neurodegenerative diseases including AD. Attenuation of glutamate toxicity is one of the therapeutic strategies for AD. LBPs were administrated to detect if they can prevent neurotoxicity elicited by glutamate in primary cultured neurons.166 The glutamate-induced cell death as detected by LDH assay and caspase-3-like activity assay was significantly reduced by LBPs at concentrations ranging from 10 µg/mL to 500 µg/mL. LBPs provided neuroprotection even 1 hour after exposure to glutamate. In addition to glutamate, LBPs attenuated N-methyl-D-aspartate-induced neuronal damage, and glutamate-induced phosphorylation of JNK was reduced by treatment with LBPs (Figure 13). LBPs exerted significant neuroprotective effects on cultured cortical neurons exposed to glutamate.\n\nManganese-induced neuronal injury\nManganese could induce multiple organs injury especially in brain and show obvious cognitive and memory deficits. A study focused on the therapeutic effect of LBPs on neurogenesis and learning and memory of manganese poisoned mice. Healthy adult Kunming mice were used. The spatial learning and memory capacity of mice was determined by the Morris water maze training test. The neurogenic cells were labeled with bromodeoxyuridine (BrdU) and detected by immunohistochemistry. The average escape latency was significantly higher and the times of passing through platform were lower in the manganese treated group. BrdU-positive cells in the LBPs-treated group were significantly more than those in the manganese-treated group. The author suggested that LBPs could enhance the learning and memory capability of the manganese poisoned mice by promoting neurogenesis in the hippocampus.167\n\nHomocysteine-induced neuronal injury\nPrevious clinical and epidemiological studies have suggested that elevated plasma homocysteine levels increased the risk of AD.168 Homocysteine damages neurons by inducing apoptosis, DNA fragmentation, and Tau phosphorylation.169 Ho et al170 conducted in vitro and in vivo studies to study the beneficial effects of LBPs on neurotoxicity caused by homocysteine. LBA treatment significantly attenuated homocysteine-induced neuronal cell death and apoptosis in primary rat cortical neurons as determined by LDH release and caspase-3 activity assays. LBPs also significantly reduced homocysteine-induced phosphorylation of Tau-1 at Ser198/199/202, pS396 at Ser396, and pS214 at Ser214 as well as cleavage of Tau.170 LBP treatment suppressed elevation of both phosphorylated extracellular-signal-regulated kinases (Erk1/2) and phosphorylated JNK. However, the phosphorylation level of GSK3β at Ser9/Tyr 216 remained unchanged among different treatment groups. The data demonstrated that LBPs exerted neuroprotective effects on cortical neurons exposed to homocysteine via modulation of JNK and Erk1/2 pathways (Figure 14).\n\nHigh ambient temperature\nYang et al171 investigated the effects of LBPs on the expression of neuropeptide Y (NPY) mRNA level in the hypothalamus, plasma concentration of corticotropin-releasing hormone (CRH), cortisol, HSP70, and epinephrine in rats subject to high ambient temperature. Compared to the control group, the plasma levels of CRH, cortisol, HSP70, and epinephrine were markedly increased, and the level of NPY mRNA was downregulated in the high ambient temperature-exposed rats.171 These effects were significantly reversed by LBP treatment in rats. LBPs have a potentially protective function against high temperature by increasing the expression of HSP70 and NPY.\n\nTraumatic neuroma\nTraumatic neuromas are tumors produced by a reactive process to regenerate injured nerves that result in a disordered proliferation of nerve bundles. These tumors are usually related to previous surgery or trauma. Fan et al172 investigated the effects of LBPs on the formation of traumatic neuroma and pain after transection of sciatic nerve in rats. LBPs were intraperitoneally injected to the rats for 28 days. The study showed that there was less neuroma formed in the LBP-treated group than in the control group. Data from transmission electron microscopy showed that there were numerous axons in nerve tumor, more fusoid fibroblasts, more collagen fiber, and hyperplasia and degenerated myelin sheath in the control group, while in the LBP-treated group, there was less myelin sheath in the proximal end of injuring nerves, less Schwann cells and fibroblasts, and sparsed collagen fibers. LBPs can inhibit autophagy and the formation of traumatic neuroma after transection of sciatic nerve in rats.\n"}

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effects and effects on cognitive and memory deficits, AD, and stroke\nAs the aged population dramatically increases in these decades, there is a great increase in the prevalence of age-associated neurodegenerative diseases such as cognitive and memory deficits, AD, and Parkinson’s disease. There is increased interest in seeking new therapeutic agents for these devastating diseases from herbal medicines. LBPs possess neuroprotective effects in various in vitro and in vivo models152–154 but the mechanisms have not yet been fully elucidated. In the nervous system, LBPs can protect against neuronal injury or loss induced by I/R,155,156 Aβ peptide,157,158 glutamate excitotoxicity, and other neurotoxic insults.154 LBPs also enhance neurogenesis.154,159\n\nIschemic brain disease and MCAO\nIschemic stroke has become one of the most devastating diseases, which cause high rates of disability and mortality in aged people.160–162 Acute excitotoxicity, oxidative stress, and inflammation are the three primary mechanisms involved in cell death during ischemic stroke.163 Cerebral edema is a detrimental feature after ischemic stroke and is one of the impact factors of clinical deterioration within the first 24 hours after stroke onset. Cerebral ischemia and reperfusion triggers a cascade of cellular events including cell death, oxidative stress, and inflammation, which all contribute to the breakdown of blood–brain barrier (BBB).160–162 Neuronal cell apoptosis plays an important role in the development of ischemic injury in the brain tissue. Mitochondrial apoptotic pathway is a major apoptotic pathway, and a large number of apoptosis-related proteins in mitochondria play an important role in the initiation and development of neuronal apoptosis.164 Pro-apoptotic and anti-apoptotic Bcl-2 family proteins play important roles in mitochondrial apoptotic pathway. Bax is a pro-apoptotic and Bcl-2 is an anti-apoptotic protein in the Bcl-2 family. Cytochrome C binds and activates apoptotic protease-activating factor-1 as well as procaspase-9, forming an apoptosome together with ATP. Apoptosome then activates caspase-9, leading to caspase-3 activation and eventually cellular apoptosis. Caspase-3 has been identified as a key mediator of apoptosis and cleaves the substrate PARP-1, which is a multifunctional nuclear enzyme whose activity is rapidly stimulated by DNA breaks.\nThe protective effect of LBPs was investigated in primary cultured rat hippocampal neurons subject to oxygen–glucose deprivation/reperfusion by Rui et al.153 Cultured hippocampal neurons were exposed to oxygen–glucose deprivation for 2 hours followed by a 24-hour re-oxygenation. Treatment with LBPs (10–40 mg/L) significantly attenuated neuronal damage and inhibited LDH release in a dose-dependent manner.153\nYang et al155 investigated the protective effect of LBP pre-treatment in an experimental stroke (MCAO) model in male C57BL/6N mice. To gain LBPs, dry L. barbarum residues were dissolved in water at 70°C, and the supernatant was concentrated, precipitated with 95% ethanol, and then vacuum dried to produce the extracts. The mice were administered 1 mg/kg or 10 mg/kg LBPs daily for 7 days, and then subjected to 2-hour transient MCAO by the intraluminal method followed by 22-hour reperfusion upon filament removal. LBP pre-treatment dose-dependently improved neurological deficits; decreased infarct size, apoptotic neurons in ischemic penumbra area, and cerebral edema; and protected the brain from BBB disruption as indicated by reduced Evans Blue dye leakage into the ipsilateral hemispheres and an upregulation of occludin expression.155 Occludin, one of the proteins located at tight junctions, plays an important role in maintaining the integrity of BBB. Pre-treatment with 10 mg/kg LBPs for 7 days also profoundly suppressed the upregulation of AQP4 expression in ipsi-lateral penumbral areas.155 Furthermore, 10 mg/kg LBPs suppressed GFAP activation in ipsilateral penumbral areas. Pre-treatment with 10 mg/kg LBPs reduced both nitrosative stress and lipid peroxidation in cerebral ischemic penumbra after MCAO. LBPs at both doses attenuated the expression of matrix metalloproteinase-9 (MMP-9) in ipsilateral penumbral areas.155 These findings clearly demonstrate the beneficial prophylactic effects of LBPs against ischemic damage and cerebral edema in a murine experimental stroke model. The neuroprotective effects of LBPs on ischemic stroke include reduction of neuronal damage and infarct, maintenance of BBB integrity, and alleviation of cerebral edema through antioxidation, suppression of upregulated MMP-9 and AQP4, anti-apoptosis, and inhibition of glial activation.\nIn a study using male Kunming mice, Wang et al165 examined the effect of intragastric administration with LBPs on brain injuries in MCAO mice. The study demonstrated that LBPs at doses of 20 mg/kg and 40 mg/kg significantly decreased the neurological deficit scores and the infarct area in MCAO mice. LBPs also significantly decreased MDA content, and increased SOD, GPx, CAT, and LDH activities in the ischemic brain.165 These findings suggest that LBPs might act as potential neuroprotective agent against the cerebral reperfusion-induced brain injury through reducing lipid peroxides, scavenging free radicals, and improving the energy metabolism.\nIn a similar study, Wang et al156 used male Imprinting Control Region mice to make the model of MCAO and investigated the protective effect of intragastric administration of 10 mg/kg, 20 mg/kg, and 40 mg/kg body weight LBPs or 0.4 mg/kg nimodipine for 7 days on MCAO-induced brain injuries. The results showed that intragastric administration of 20 mg/kg and 40 mg/kg LBPs markedly decreased the neurological deficit scores and the infarct volume in MCAO mice.156 Administration of 10–40 mg/kg LBPs also reduced neuronal morphological damage and neuronal apoptosis in ischemic penumbra of the left cortex. About 40 mg/kg LBPs significantly suppressed cortex overexpression of Bax, cytochrome C, caspase-3, -9, and cleaved PARP-1, and reduced the downregulated Bcl-2 expression in MCAO mice.156\nIn summary, the protective effects of LBPs on MCAO-induced brain injuries are mainly attributed to the reduction of oxidative stress, inhibition of apoptosis, and increase in the integrity of BBB. LBPs treatment reduces the oxidative stress via increasing the SOD, GPx, CAT, and LDH activities, but decreasing the content of MDA and lipid peroxidation. LBPs also inhibit the apoptosis via decreasing the expression of cytochrome C, cleave caspase-9, caspase-3, Bax, and cleaved PARP-1, but increasing the expression level of Bcl-2. In addition, LBPs increase the integrity of BBB expression through the upregulation of expression of occludin, but downregulation of the expression of MMP-9 and AQP4 (Figure 10).\n\nAβ-induced neuronal injury and AD\nAβ peptides are thought to be associated with the progressive neuronal death observed in AD. The effect of LBPs was investigated by Yu et al157 on the neuronal injury induced by Aβ1-42 and Aβ25-35 peptides in primary rat cortical neurons. Remarkable apoptosis and necrosis in primary rat cortical neurons were observed when exposed to Aβ peptides. Pre-treatment with LBPs significantly reduced the release of LDH. In addition, LBPs attenuated Aβ peptide-activated caspase-3-like activity.157 Aβ peptides induce a rapid activation of c-JNK by phosphorylation. Pre-treatment of LBPs markedly reduced the phosphorylation of JNK-1 at Thr183/Tyr185 and its substrates c-Jun-I at Ser73 and c-Jun-II at Ser63.157 LPBs elicit dose-dependent neuroprotective effects via regulation of JNK-1 pathway.\nYu et al158 also investigated the effects of LBPs on the phosphorylation of the double-stranded RNA-dependent protein kinase (PKR) in rat cortical neurons exposed to Aβ peptides. PKR is an intracellular sensor of stress and can arrest protein synthesis by phosphorylating the alpha subunit of the translation initiation factor eIF2. Pretreatment of LBPs effectively protected neurons against Aβ-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. LBPs markedly reduced Aβ-induced PKR phosphorylation.158\nIn summary, LBPs protect neurons against Aβ-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9 (Figure 11). LBPs inhibit the phosphorylation of JNK-1 at Thr183/Tyr185 and its substrates c-Jun-I at Ser73 and c-Jun-II at Ser63 in neurons. LBPs reduce the phosphorylation of Erk1/2m but not GSK3β. LBPs also markedly reduced Aβ-induced PKR phosphorylation. LBPs also significantly reduce homocysteine-induced phosphorylation of Tau-1 at Ser198/199/202, pS396 at Ser396, and pS214 at Ser214 as well as cleavage of Tau.\n\nScopolamine-induced brain injury\nA recent study by Chen et al154 reported the therapeutic effects of LBPs on learning and memory and neurogenesis in scopolamine (SCO)-treated adult male Sprague–Dawley rats. SCO was used to induce learning and memory deficits. LBPs were administered 0.2 mg/kg or 1 mg/kg body weight per day via gastric perfusion for 14 days before the onset of subcutaneous SCO treatment for a further 4 weeks. LBPs used were extracted with boiling water, followed by precipitation with ethanol, protein hydrolysis, dialysis, and fractionation with a diethylaminoethanol-Sepharose CL-6B column. An osmotic pump containing SCO solution at 440 mg/mL was subcutaneously embedded in the abdominal wall of rats and SCO release at a rate of 0.25 µL/h was maintained for 28 days and administration of LBPs was continued as before, throughout SCO treatment. LBPs at both doses almost restored the memory and learning abilities in SCO-treated rats.154 LBPs prevented SCO-induced reduction in neuronal proliferation and enhanced neuroblast differentiation in the hippocampal dentate gyrus of rats.\nLBP treatment also protected the dendrites from damage by SCO. LBPs dose-dependently decreased the SCO-induced oxidative stress in hippocampus and reversed the increased ratio of Bax/Bcl-2 induced by SCO treatment.154 LBPs significantly increased hippocampal SOD and GPx activity and reduced MDA level in SCO-treated rats. However, LBPs did not affect the SCO-induced elevation of hippocampal acetylcholinesterase activity and decrease of brain-derived neurotrophic factor level.154 These results suggest that LBPs prevent SCO-induced cognitive and memory impairments and reductions in hippocampal cell proliferation and neuroblast differentiation. Anti-oxidation and anti-apoptosis are the two major mechanisms for the neuroprotective effects of LBPs in SCO-treated rats (Figure 12).\n\nGlutamate-induced neuronal injury\nGlutamate excitotoxicity is involved in many neurodegenerative diseases including AD. Attenuation of glutamate toxicity is one of the therapeutic strategies for AD. LBPs were administrated to detect if they can prevent neurotoxicity elicited by glutamate in primary cultured neurons.166 The glutamate-induced cell death as detected by LDH assay and caspase-3-like activity assay was significantly reduced by LBPs at concentrations ranging from 10 µg/mL to 500 µg/mL. LBPs provided neuroprotection even 1 hour after exposure to glutamate. In addition to glutamate, LBPs attenuated N-methyl-D-aspartate-induced neuronal damage, and glutamate-induced phosphorylation of JNK was reduced by treatment with LBPs (Figure 13). LBPs exerted significant neuroprotective effects on cultured cortical neurons exposed to glutamate.\n\nManganese-induced neuronal injury\nManganese could induce multiple organs injury especially in brain and show obvious cognitive and memory deficits. A study focused on the therapeutic effect of LBPs on neurogenesis and learning and memory of manganese poisoned mice. Healthy adult Kunming mice were used. The spatial learning and memory capacity of mice was determined by the Morris water maze training test. The neurogenic cells were labeled with bromodeoxyuridine (BrdU) and detected by immunohistochemistry. The average escape latency was significantly higher and the times of passing through platform were lower in the manganese treated group. BrdU-positive cells in the LBPs-treated group were significantly more than those in the manganese-treated group. The author suggested that LBPs could enhance the learning and memory capability of the manganese poisoned mice by promoting neurogenesis in the hippocampus.167\n\nHomocysteine-induced neuronal injury\nPrevious clinical and epidemiological studies have suggested that elevated plasma homocysteine levels increased the risk of AD.168 Homocysteine damages neurons by inducing apoptosis, DNA fragmentation, and Tau phosphorylation.169 Ho et al170 conducted in vitro and in vivo studies to study the beneficial effects of LBPs on neurotoxicity caused by homocysteine. LBA treatment significantly attenuated homocysteine-induced neuronal cell death and apoptosis in primary rat cortical neurons as determined by LDH release and caspase-3 activity assays. LBPs also significantly reduced homocysteine-induced phosphorylation of Tau-1 at Ser198/199/202, pS396 at Ser396, and pS214 at Ser214 as well as cleavage of Tau.170 LBP treatment suppressed elevation of both phosphorylated extracellular-signal-regulated kinases (Erk1/2) and phosphorylated JNK. However, the phosphorylation level of GSK3β at Ser9/Tyr 216 remained unchanged among different treatment groups. The data demonstrated that LBPs exerted neuroprotective effects on cortical neurons exposed to homocysteine via modulation of JNK and Erk1/2 pathways (Figure 14).\n\nHigh ambient temperature\nYang et al171 investigated the effects of LBPs on the expression of neuropeptide Y (NPY) mRNA level in the hypothalamus, plasma concentration of corticotropin-releasing hormone (CRH), cortisol, HSP70, and epinephrine in rats subject to high ambient temperature. Compared to the control group, the plasma levels of CRH, cortisol, HSP70, and epinephrine were markedly increased, and the level of NPY mRNA was downregulated in the high ambient temperature-exposed rats.171 These effects were significantly reversed by LBP treatment in rats. LBPs have a potentially protective function against high temperature by increasing the expression of HSP70 and NPY.\n\nTraumatic neuroma\nTraumatic neuromas are tumors produced by a reactive process to regenerate injured nerves that result in a disordered proliferation of nerve bundles. These tumors are usually related to previous surgery or trauma. Fan et al172 investigated the effects of LBPs on the formation of traumatic neuroma and pain after transection of sciatic nerve in rats. LBPs were intraperitoneally injected to the rats for 28 days. The study showed that there was less neuroma formed in the LBP-treated group than in the control group. Data from transmission electron microscopy showed that there were numerous axons in nerve tumor, more fusoid fibroblasts, more collagen fiber, and hyperplasia and degenerated myelin sheath in the control group, while in the LBP-treated group, there was less myelin sheath in the proximal end of injuring nerves, less Schwann cells and fibroblasts, and sparsed collagen fibers. LBPs can inhibit autophagy and the formation of traumatic neuroma after transection of sciatic nerve in rats.\n"}