Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes... more Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes, and dyslipidemia and insulin resistance (IR) is the central feature of MetS. Recent studies suggest that MetS is a risk factor for Alzheimer's disease (AD). AMP-activated kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme and a key player in regulating energy metabolism. In this report we examined the role of IR on the regulation of AMPK phosphorylation and AMPK-mediated tau phosphorylation. We found that AMPK(Ser485), but not AMPK(Thr172), phosphorylation is increased in the cortex of db/db and high fat diet-fed obese mice, two mouse models of IR. In vitro, treatment of human cortical stem cell line (HK-5320) and primary mouse embryonic cortical neurons with the AMPK activator, AICAR, induced AMPK phosphorylation at both Thr172 and Ser485. AMPK activation also triggered tau dephosphorylation. When IR was mimicked in vitro by chronically treating the cells with insulin, AICAR specifically induced AMPK(Ser485), but not AMPK(Thr172), hyperphosphorylation whereas AICAR-induced tau dephosphorylation was inhibited. IR also resulted in the overactivation of Akt by AICAR treatment; however, preventing Akt overactivation during IR prevented AMPK(Ser485) hyperphosphorylation and restored AMPK-mediated tau dephosphorylation. Transfection of AMPK(S485A) mutant caused similar results. Therefore, our results suggest the following mechanism for the adverse effect of IR on AD pathology: IR → chronic overactivation of Akt → AMPK(Ser485) hyperphosphorylation → inhibition of AMPK-mediated tau dephosphorylation. Together, our results show for the first time a possible contribution of IR-induced AMPK(Ser485) phosphorylation to the increased risk of AD in obesity and diabetes.
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diab... more Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR an...
A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may... more A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. The results indicate that insulin signaling abnormalities documented in other "insulin sensitive" tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the P...
Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherite... more Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals. Presymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate sympt...
An interim report of a case-control study was conducted to explore the role of environmental fact... more An interim report of a case-control study was conducted to explore the role of environmental factors in the development of amyotrophic lateral sclerosis (ALS). Sixty-six cases and 66 age- and gender-matched controls were recruited. Detailed information regarding residence history, occupational history, smoking, physical activity, and other factors was obtained using questionnaires. The association of ALS with potential risk factors, including smoking, physical activity and chemical exposure, was investigated using conditional logistic regression models. As compared to controls, a greater number of our randomly selected ALS patients reported exposure to fertilizers to treat private yards and gardens and occupational exposure to pesticides in the last 30 years than our randomly selected control cases. Smoking, occupational exposures to metals, dust/fibers/fumes/gas and radiation, and physical activity were not associated with ALS when comparing the randomly selected ALS patients to th...
The publication of the Diabetes Control and Complications Trial (DCCT) laid to rest much of the c... more The publication of the Diabetes Control and Complications Trial (DCCT) laid to rest much of the controversy surrounding the role of hyperglycemia in diabetic neuropathy. This study showed that intensive insulin therapy, coupled with improved glycemic control, reduces the severity of diabetic complications and, more importantly, decreases the risk of developing these complications. This was the first large prospective study to show that careful regulation of blood glucose can prevent development of neuropathy in diabetic patients. Despite the evidence that hyperglycemia is coupled with neuropathy, it has been assumed that neuropathy results only from significant hyperglycemia and is not related to impaired glucose tolerance (IGT). In the presence of mild and episodic hyperglycemia, alternative causes for neuropathy are sought.
The human neuroblastoma line, SK-N-SH, has been subcloned into SH-SY5Y, a neuroblast N cell line,... more The human neuroblastoma line, SK-N-SH, has been subcloned into SH-SY5Y, a neuroblast N cell line, and SH-EP, an epithelial Schwann S cell line. We have previously shown that SH-SY5Y neuroblastoma cells produce insulin-like growth factor II (IGF-II), which acts by an autocrine mechanism to stimulate cell growth. In the current study, we examined the effect of IGF-II on SH-EP neuroblastoma
Background: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes... more Background: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1 G93A rats leads to a moderate therapeutical effect as evidenced by local a-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1 G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1 G93A animals.
Motility is an important process that contributes to cancer cell spread. Growth factors are key r... more Motility is an important process that contributes to cancer cell spread. Growth factors are key regulators of motility in many cell types. Insulin-like growth factor I (IGF-I) causes SH-SY5Y human neuroblastoma cells to undergo dynamic morphological changes, leading to the extension of lamellipodia. IGF-I stimulated lamellipodia extension requires signaling through both phosphatidylinositol 3-kinase (PI3-K) and MAP kinase pathways. IGF-I, over a period of hours, stimulates SH-SY5Y and SHEP neuroblastoma cells to become more motile. While SH-SY5Y and SHEP cells use dierent insulin receptor substrate (IRS) isoforms to transduce signals from the IGF-I receptor, IGF-I has the same relative eect on the motility of both cell lines. Blocking the PI3-K and MAP kinase pathways attenuates the ability of IGF-I to increase motility. Overexpression of PTEN also attenuates IGF-I mediated motility. These results delineate some of the proximal events in the signaling mechanism utilized by IGF-I to stimulate cell motility. Oncogene (2001) 20, 7542 ± 7550.
Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for... more Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; and non-pharmacological: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulphate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. PM R 2011;3:345-352 Diabetic sensorimotor polyneuropathy represents a diffuse symmetrical and length-dependent injury to peripheral nerves that has major implications on quality of life (QOL), morbidity, and costs from a public health perspective [1,2]. Painful diabetic neuropathy (PDN) affects 16% of patients with diabetes, and it is frequently unreported (12.5%) and more frequently untreated (39%) . PDN presents an ongoing management problem for patients, caregivers, and physicians. There are many treatment options available, and a rational approach to treating the patient with PDN requires an understanding of the evidence for each intervention. This guideline addresses the efficacy of pharmacological and nonpharmacological treatments to reduce pain and improve physical function and QOL in patients with PDN. The pharmacological agents reviewed include anticonvulsants, antidepressants, opioids, antiarrhythmics, cannabinoids, aldose reductase inhibitors, protein kinase C beta inhibitors, antioxidants (alpha lipoic acid), transketolase activators (thiamines and allithiamines), topical medications (analgesic patches, anesthetic patches, capsaicin cream, clonidine), and others. The nonpharmacological modalities include infrared therapy, shoe magnets, exercise, acupuncture, external stimulation (TENS), spinal cord stimulation, biofeedback and behavioral therapy, surgical decompression, and intrathecal baclofen.
Insulin-like growth factor I (IGF-I) and IGF-II are potent trophic factors for motor and sensory ... more Insulin-like growth factor I (IGF-I) and IGF-II are potent trophic factors for motor and sensory neurons and glial cells. The actions of IGF-I and IGF-II are mediated via the IGF-I receptor (IGF-IR). IGF:IGF-IR binding activates distinct signaling cascades, which in turn mediate the trophic effects of the IGFs. We discuss three main IGF coupled events: growth cone motility, long-term neurite outgrowth, and neuroprotection. Our data suggest that IGF-I enhances growth cone motility by promoting reorganization of actin and activation of focal adhesion proteins via the phosphatidylinositol-3 kinase (Pl-3K) pathway. Long-term treatment with IGF-I activates the mitogen-activated protein (MAP) kinase cascade and promotes neurite outgrowth. A separable, but likely linked, action of the IGFs via Pl-3K is protection of neurons from apoptosis. These pleotrophic effects of IGFs suggest that this family of growth factors may have potential clinical utility in the treatment of neurological disorders.
Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the l... more Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death caspase pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.
The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malign... more The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malignancy NB 2 , Bcl-2 is highly expressed. In tumors with a poor prognosis, N-Myc, a protein homologous to c-Myc, is overexpressed as a result of gene amplification. The present study was ...
Engineered zinc-finger protein (ZFP) transcription factors induce the expression of endogenous ge... more Engineered zinc-finger protein (ZFP) transcription factors induce the expression of endogenous genes and can be remotely delivered using adenoviral vectors. One such factor, Ad-32Ep65-Flag (Ad-p65), targets and induces expression of vascular endothelial growth factor (VEGF; also called VEGF-A) splice variants in their normal biological stoichiometry. We show that Ad-p65 transfection of primary motor neurons results in VEGF variant expression and a significant increase in axon outgrowth in these cells. Given the neuroprotective effects of VEGF and its ability to increase neurite outgrowth, we examined the efficacy of Ad-p65 to enhance motor neuron regeneration in vivo using rats that have undergone recurrent laryngeal nerve (RLN)-crush injury. Injection of Ad-p65 after RLN crush accelerated the return of vocal fold mobility and the percentage of nerve-endplate contacts in the thyroarytenoid muscle. Overall, adenoviral delivery of an engineered ZFP transcription factor inducing VEGF-A splice variant expression enhances nerve regeneration. ZFP transcription factor gene therapy to increase expression of the full complement of VEGF-A splice variants is a promising avenue for the treatment of nerve injury and neurodegeneration.
OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, plac... more OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and type 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.
ABSTRACT: Insulin-like growth factor-I (IGF-NGF withdrawal. The antiapoptotic effect of IGF-I I) ... more ABSTRACT: Insulin-like growth factor-I (IGF-NGF withdrawal. The antiapoptotic effect of IGF-I I) is emerging as an important growth factor able to was completely blocked by LY294002, an inhibitor of modulate the programmed cell death (PCD) pathway mediated by the cysteine-dependent aspartate prote-PI 3-kinase signaling, but not by the mitogen-activated ases (caspases); however, little is known about the protein (MAP) kinase/extracellular signal-regulated effect of IGF-I after nerve growth factor (NGF) withprotein kinase (ERK) activated protein kinase inhibidrawal in neurons. To begin to understand the neutor PD98059. Functional IGF-I receptors were extenronal death-sparing effect of IGF-I under NGF-free sively expressed both in rat and human DRG neurons, conditions, we tested whether embryonic sensory doralthough they were most abundant in the neuronal sal root ganglion neurons (DRG) were able to survive growth cone. Collectively, these findings indicate that in defined serum-free medium in the presence of IGF-IGF-I, signaling though the PI-3 kinase pathway, is I. We further studied the role of IGF-I signaling and important in modulating PCD in cultured DRG neucaspase inhibition after NGF withdrawal. NGF withrons after NGF withdrawal, and IGF-I may be imdrawal produced histological changes of apoptosis inportant in DRG embryogenesis. ᭧ 1998 John Wiley & cluding chromatin condensation, shrinkage of the per- Sons, Inc. J Neurobiol 36: 455-467, 1998 ikaryon and nucleus, retention of the plasma mem-
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes... more Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes, and dyslipidemia and insulin resistance (IR) is the central feature of MetS. Recent studies suggest that MetS is a risk factor for Alzheimer's disease (AD). AMP-activated kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme and a key player in regulating energy metabolism. In this report we examined the role of IR on the regulation of AMPK phosphorylation and AMPK-mediated tau phosphorylation. We found that AMPK(Ser485), but not AMPK(Thr172), phosphorylation is increased in the cortex of db/db and high fat diet-fed obese mice, two mouse models of IR. In vitro, treatment of human cortical stem cell line (HK-5320) and primary mouse embryonic cortical neurons with the AMPK activator, AICAR, induced AMPK phosphorylation at both Thr172 and Ser485. AMPK activation also triggered tau dephosphorylation. When IR was mimicked in vitro by chronically treating the cells with insulin, AICAR specifically induced AMPK(Ser485), but not AMPK(Thr172), hyperphosphorylation whereas AICAR-induced tau dephosphorylation was inhibited. IR also resulted in the overactivation of Akt by AICAR treatment; however, preventing Akt overactivation during IR prevented AMPK(Ser485) hyperphosphorylation and restored AMPK-mediated tau dephosphorylation. Transfection of AMPK(S485A) mutant caused similar results. Therefore, our results suggest the following mechanism for the adverse effect of IR on AD pathology: IR → chronic overactivation of Akt → AMPK(Ser485) hyperphosphorylation → inhibition of AMPK-mediated tau dephosphorylation. Together, our results show for the first time a possible contribution of IR-induced AMPK(Ser485) phosphorylation to the increased risk of AD in obesity and diabetes.
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diab... more Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR an...
A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may... more A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. The results indicate that insulin signaling abnormalities documented in other "insulin sensitive" tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the P...
Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherite... more Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals. Presymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate sympt...
An interim report of a case-control study was conducted to explore the role of environmental fact... more An interim report of a case-control study was conducted to explore the role of environmental factors in the development of amyotrophic lateral sclerosis (ALS). Sixty-six cases and 66 age- and gender-matched controls were recruited. Detailed information regarding residence history, occupational history, smoking, physical activity, and other factors was obtained using questionnaires. The association of ALS with potential risk factors, including smoking, physical activity and chemical exposure, was investigated using conditional logistic regression models. As compared to controls, a greater number of our randomly selected ALS patients reported exposure to fertilizers to treat private yards and gardens and occupational exposure to pesticides in the last 30 years than our randomly selected control cases. Smoking, occupational exposures to metals, dust/fibers/fumes/gas and radiation, and physical activity were not associated with ALS when comparing the randomly selected ALS patients to th...
The publication of the Diabetes Control and Complications Trial (DCCT) laid to rest much of the c... more The publication of the Diabetes Control and Complications Trial (DCCT) laid to rest much of the controversy surrounding the role of hyperglycemia in diabetic neuropathy. This study showed that intensive insulin therapy, coupled with improved glycemic control, reduces the severity of diabetic complications and, more importantly, decreases the risk of developing these complications. This was the first large prospective study to show that careful regulation of blood glucose can prevent development of neuropathy in diabetic patients. Despite the evidence that hyperglycemia is coupled with neuropathy, it has been assumed that neuropathy results only from significant hyperglycemia and is not related to impaired glucose tolerance (IGT). In the presence of mild and episodic hyperglycemia, alternative causes for neuropathy are sought.
The human neuroblastoma line, SK-N-SH, has been subcloned into SH-SY5Y, a neuroblast N cell line,... more The human neuroblastoma line, SK-N-SH, has been subcloned into SH-SY5Y, a neuroblast N cell line, and SH-EP, an epithelial Schwann S cell line. We have previously shown that SH-SY5Y neuroblastoma cells produce insulin-like growth factor II (IGF-II), which acts by an autocrine mechanism to stimulate cell growth. In the current study, we examined the effect of IGF-II on SH-EP neuroblastoma
Background: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes... more Background: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1 G93A rats leads to a moderate therapeutical effect as evidenced by local a-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1 G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1 G93A animals.
Motility is an important process that contributes to cancer cell spread. Growth factors are key r... more Motility is an important process that contributes to cancer cell spread. Growth factors are key regulators of motility in many cell types. Insulin-like growth factor I (IGF-I) causes SH-SY5Y human neuroblastoma cells to undergo dynamic morphological changes, leading to the extension of lamellipodia. IGF-I stimulated lamellipodia extension requires signaling through both phosphatidylinositol 3-kinase (PI3-K) and MAP kinase pathways. IGF-I, over a period of hours, stimulates SH-SY5Y and SHEP neuroblastoma cells to become more motile. While SH-SY5Y and SHEP cells use dierent insulin receptor substrate (IRS) isoforms to transduce signals from the IGF-I receptor, IGF-I has the same relative eect on the motility of both cell lines. Blocking the PI3-K and MAP kinase pathways attenuates the ability of IGF-I to increase motility. Overexpression of PTEN also attenuates IGF-I mediated motility. These results delineate some of the proximal events in the signaling mechanism utilized by IGF-I to stimulate cell motility. Oncogene (2001) 20, 7542 ± 7550.
Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for... more Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; and non-pharmacological: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulphate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. PM R 2011;3:345-352 Diabetic sensorimotor polyneuropathy represents a diffuse symmetrical and length-dependent injury to peripheral nerves that has major implications on quality of life (QOL), morbidity, and costs from a public health perspective [1,2]. Painful diabetic neuropathy (PDN) affects 16% of patients with diabetes, and it is frequently unreported (12.5%) and more frequently untreated (39%) . PDN presents an ongoing management problem for patients, caregivers, and physicians. There are many treatment options available, and a rational approach to treating the patient with PDN requires an understanding of the evidence for each intervention. This guideline addresses the efficacy of pharmacological and nonpharmacological treatments to reduce pain and improve physical function and QOL in patients with PDN. The pharmacological agents reviewed include anticonvulsants, antidepressants, opioids, antiarrhythmics, cannabinoids, aldose reductase inhibitors, protein kinase C beta inhibitors, antioxidants (alpha lipoic acid), transketolase activators (thiamines and allithiamines), topical medications (analgesic patches, anesthetic patches, capsaicin cream, clonidine), and others. The nonpharmacological modalities include infrared therapy, shoe magnets, exercise, acupuncture, external stimulation (TENS), spinal cord stimulation, biofeedback and behavioral therapy, surgical decompression, and intrathecal baclofen.
Insulin-like growth factor I (IGF-I) and IGF-II are potent trophic factors for motor and sensory ... more Insulin-like growth factor I (IGF-I) and IGF-II are potent trophic factors for motor and sensory neurons and glial cells. The actions of IGF-I and IGF-II are mediated via the IGF-I receptor (IGF-IR). IGF:IGF-IR binding activates distinct signaling cascades, which in turn mediate the trophic effects of the IGFs. We discuss three main IGF coupled events: growth cone motility, long-term neurite outgrowth, and neuroprotection. Our data suggest that IGF-I enhances growth cone motility by promoting reorganization of actin and activation of focal adhesion proteins via the phosphatidylinositol-3 kinase (Pl-3K) pathway. Long-term treatment with IGF-I activates the mitogen-activated protein (MAP) kinase cascade and promotes neurite outgrowth. A separable, but likely linked, action of the IGFs via Pl-3K is protection of neurons from apoptosis. These pleotrophic effects of IGFs suggest that this family of growth factors may have potential clinical utility in the treatment of neurological disorders.
Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the l... more Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death caspase pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.
The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malign... more The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malignancy NB 2 , Bcl-2 is highly expressed. In tumors with a poor prognosis, N-Myc, a protein homologous to c-Myc, is overexpressed as a result of gene amplification. The present study was ...
Engineered zinc-finger protein (ZFP) transcription factors induce the expression of endogenous ge... more Engineered zinc-finger protein (ZFP) transcription factors induce the expression of endogenous genes and can be remotely delivered using adenoviral vectors. One such factor, Ad-32Ep65-Flag (Ad-p65), targets and induces expression of vascular endothelial growth factor (VEGF; also called VEGF-A) splice variants in their normal biological stoichiometry. We show that Ad-p65 transfection of primary motor neurons results in VEGF variant expression and a significant increase in axon outgrowth in these cells. Given the neuroprotective effects of VEGF and its ability to increase neurite outgrowth, we examined the efficacy of Ad-p65 to enhance motor neuron regeneration in vivo using rats that have undergone recurrent laryngeal nerve (RLN)-crush injury. Injection of Ad-p65 after RLN crush accelerated the return of vocal fold mobility and the percentage of nerve-endplate contacts in the thyroarytenoid muscle. Overall, adenoviral delivery of an engineered ZFP transcription factor inducing VEGF-A splice variant expression enhances nerve regeneration. ZFP transcription factor gene therapy to increase expression of the full complement of VEGF-A splice variants is a promising avenue for the treatment of nerve injury and neurodegeneration.
OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, plac... more OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and type 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.
ABSTRACT: Insulin-like growth factor-I (IGF-NGF withdrawal. The antiapoptotic effect of IGF-I I) ... more ABSTRACT: Insulin-like growth factor-I (IGF-NGF withdrawal. The antiapoptotic effect of IGF-I I) is emerging as an important growth factor able to was completely blocked by LY294002, an inhibitor of modulate the programmed cell death (PCD) pathway mediated by the cysteine-dependent aspartate prote-PI 3-kinase signaling, but not by the mitogen-activated ases (caspases); however, little is known about the protein (MAP) kinase/extracellular signal-regulated effect of IGF-I after nerve growth factor (NGF) withprotein kinase (ERK) activated protein kinase inhibidrawal in neurons. To begin to understand the neutor PD98059. Functional IGF-I receptors were extenronal death-sparing effect of IGF-I under NGF-free sively expressed both in rat and human DRG neurons, conditions, we tested whether embryonic sensory doralthough they were most abundant in the neuronal sal root ganglion neurons (DRG) were able to survive growth cone. Collectively, these findings indicate that in defined serum-free medium in the presence of IGF-IGF-I, signaling though the PI-3 kinase pathway, is I. We further studied the role of IGF-I signaling and important in modulating PCD in cultured DRG neucaspase inhibition after NGF withdrawal. NGF withrons after NGF withdrawal, and IGF-I may be imdrawal produced histological changes of apoptosis inportant in DRG embryogenesis. ᭧ 1998 John Wiley & cluding chromatin condensation, shrinkage of the per- Sons, Inc. J Neurobiol 36: 455-467, 1998 ikaryon and nucleus, retention of the plasma mem-
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Papers by Eva Feldman