Parkinson Disease: Hoffer BJ

Harvey BK, Wang Y, Hoffer BJ. · Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore 21224, MD, USA. · Acta Neurochir Suppl. · Pubmed #18642640 links to  free full text

Abstract: In the case of Parkinson's disease (PD), classical animal models have utilized dopaminergic neurotoxins such as 6-hydroxydopamine (6OHDA) and 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). More recently, human genetic linkage studies have identified several genes in familial forms of PD. Transgenic models have been made that explore the function of PD-linked genes (e.g. alpha-synuclein, DJ-1, LRRK2, Parkin, UCH-L1, PINK1). Recent evidence suggests mitochondrial dysfunction may play a major role in PD. Manipulation of mitochondrial respiratory genes (e.g. mitochondrial transcription factor A or TFAM) also elicits a PD phenotype in mice. Transgenic mice (MitoPark) were developed that have TFAM selectively knocked out in dopaminergic neurons. The nigral dopamine neurons of MitoPark mice show respiratory chain dysfunction, accompanied by the development of intraneuronal inclusions and eventual cell death. In early adulthood, the MitoPark mice show a slowly progressing loss of motor function that accompanies these cellular changes. The MitoPark mouse enables further study of the role of mitochondrial dysfunction in DA neurons as an important mechanism in the development of PD. Transgenic technology has allowed new insights into mechanisms of neurodegeneration for a number of neurological disorders. This paper will summarize recent studies on several transgenic models of PD.

Chiocco MJ, Harvey BK, Wang Y, Hoffer BJ. · Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. · Parkinsonism Relat Disord. · Pubmed #18267258 No free full text.

Abstract: Parkinson's disease (PD) is a slowly progressive disorder with no known etiology. Pathologically, there is a loss of the dopaminergic neurons in the substantia nigra that project to the striatum. Current available therapies for PD are targeted to the restoration of striatal dopamine. These approaches may alleviate symptoms transiently, but fail to slow the progression of disease. One emergent therapeutic approach is the use of neurotrophic factors to halt or reverse the loss of dopaminergic neurons. There have been intensive research efforts both preclinically and clinically testing the efficacy and safety of neurotrophic factors for the treatment of PD. In this review, we discuss the neuroprotective and neuroregenerative properties of various trophic factors, both old and recent, and their status as therapeutic molecules for PD.

Chiang YH, Borlongan CV, Zhou FC, Hoffer BJ, Wang Y. · Tri-Service General Hospital, National Defense Medical Center, Taiwan. · Cell Transplant. · Pubmed #15789657 No free full text.

Abstract: Various trophic factors in the transforming growth factor-beta (TGF-beta) superfamily have been reported to have neuroprotective and neuroregenerative effects. Intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) or bone morphogenetic proteins (BMPs), both members of the TGF-beta family, reduce ischemia- or 6-hydroxydopamine (6-OHDA)-induced injury in adult rat brain. Because BMPs and GDNF are highly expressed in fetal kidney cells, transplantation of fetal kidney tissue could serve as a cellular reservoir for such molecules and protect against neuronal injury induced by ischemia, neurotoxins, or reactive oxygen species. In this review, we discuss preclinical evidence for the efficacy of fetal kidney cell transplantation in neuroprotection and regeneration models.

Harvey BK, Hoffer BJ, Wang Y. · Neural Protection and Regeneration Section, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, NIH, Baltimore, MD 21124, USA. · Pharmacol Ther. · Pubmed #15670622 No free full text.

Abstract: Recent studies have indicated that proteins in the transforming growth factor-beta superfamily alter damage induced by various neuronal injuries. Of these proteins, glial cell line-derived neurotrophic factor (GDNF) and bone morphogenetic protein-7 (BMP-7) have unique protective and regenerative effects in stroke animals. Delivery of GDNF or BMP-7 to brain tissue reduced cerebral infarction and improved motor functions in stroke animals. Pretreatment with these factors reduced caspase-3 activity and DNA fragmentation in the ischemic brain region, suggesting that antiapoptotic effects are involved. Beside the protective effects, BMP-7 given after stroke improves locomotor function. These regenerative effects of BMP-7 may involve the enhancement of dendritic growth and remodeling. In this review, we illustrate the neuroprotective and neuroregenerative properties of GDNF and BMP-7 and emphasize their therapeutic potential for stroke.

Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH. · Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA. · Proc Natl Acad Sci U S A. · Pubmed #19164583 links to  free full text

Abstract: Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia- and 6-hydroxydopamine-induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD.

Zaman V, Boger HA, Granholm AC, Rohrer B, Moore A, Buhusi M, Gerhardt GA, Hoffer BJ, Middaugh LD. · Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. · Eur J Neurosci. · Pubmed #18973577 links to  free full text

Abstract: Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)alpha-1 (GFRalpha-1(+/-)), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRalpha-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRalpha-1(+/-) mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRalpha-1(+/-) mice. DA in the striatum was reduced in the GFRalpha-1(+/-) mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRalpha-1(+/-) mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRalpha-1(+/-) mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRalpha-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRalpha-1 can contribute to the degenerative changes observed in this system during the aging process.

Bäckman CM, Shan L, Zhang Y, Hoffer BJ, Tomac AC. · Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. · J Neurosci Res. · Pubmed #17203488 No free full text.

Abstract: A real-time quantitative PCR approach was used to quantify mRNA levels corresponding to the neuropeptides enkephalin, dynorphin, and the 67-kDa isoform of glutamic acid decarboxylase (GAD67) in the human putamen from young and aged individuals as well as from aged patients affected by Parkinson's disease (PD). cDNA-specific primers were designed to amplify GAD67, proenkephalin (pENK), prodynorphin (pDYN), and the housekeeping genes glyceraldehydes-3-phosphate dehydrogenase (GAPDH) and guanine nucleotide binding protein, beta-peptide 2-like I (GNB2LI). GAPDH and GNB2LI mRNA levels were similarly expressed among the groups and were therefore used as endogenous reference genes. Normalized data showed that mRNA levels for both pENK and pDYN were reduced in the putamen of aged controls and aged individuals affected by PD, compared with young controls. In addition, we showed that GAD67 mRNA levels did not change during aging and PD. Further analyses showed no differences in mRNA levels, for pENK, pDYN, or GAD67 mRNA, between PD patients and aged matched controls. These findings contrast with animal models of parkinsonism, for which expression of pDYN, pENK, and GAD67 mRNA has been reported to change after striatal dopamine denervation. Compensatory mechanisms and regional differences within the human putamen as well as the severity index of the disease, clinical diagnosis, and response to phalmacological therapy are possible reasons for these results. The present study suggests that alteration of neuropeptide pathways in the human putamen may be involved in the functional deterioration of parts of the extrapyramidal system during aging.

Bäckman CM, Shan L, Zhang YJ, Hoffer BJ, Leonard S, Troncoso JC, Vonsatel P, Tomac AC. · Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. · Mol Cell Endocrinol. · Pubmed #16644101 No free full text.

Abstract: Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta superfamily, is a potent trophic factor for dopaminergic neurons of the ventral midbrain, which are known to degenerate during Parkinson's disease (PD). The neuroprotective, neurorestorative, and stimulatory properties of GDNF has prompted numerous suggestions that this trophic factor may be a potential therapeutic tool to treat PD, and it has also been widely speculated that altered GDNF expression levels may be involved in the pathophysiology of the disease. In this study, we have investigated if mRNA expression levels for GDNF and/or its receptors are altered during PD in the human putamen, a target area for dopamine neurons of the substantia nigra compacta. Expression levels were analyzed with quantitative real-time reverse transcriptase polymerase reaction (RT qPCR) in post-mortem tissues from PD patients and aged matched controls. Primer pairs specific for GDNF (isoforms I and II), and its receptor molecules, GFRalpha1 and cRET were utilized. GDNF, cRET and GFRalpha1 mRNA expression was clearly detected in the putamen of control and Parkinson's disease patients. A modest but significant upregulation of GDNF mRNA levels (Isoform I) was observed in the putamen of Parkinson's disease patients with a marked loss of nigral neurons. No significant changes were observed for the expression of cRet and GFRa1. These data suggest that the extensive loss of dopaminergic neurons in the substantia nigra, and concomitant loss of striatal dopamine, may induce compensatory changes in the expression of target derived GDNF, but not its receptor system.

Harvey BK, Mark A, Chou J, Chen GJ, Hoffer BJ, Wang Y. · National Institute on Drug Abuse, NIH, Neural Protection and Regeneration Section, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. · Brain Res. · Pubmed #15353217 No free full text.

Abstract: Previous studies have demonstrated that pretreatment with bone morphogenetic protein-7 (BMP7) reduces ischemic neuronal injury in vivo. Moreover, exogenous application of BMP7 increases both the number of tyrosine hydroxylase (+) cells and dopamine (DA) uptake in rat mesencephalic cell cultures. The purpose of this study was to investigate the in vivo effects of BMP7 on 6-hydroxydopamine (6-OHDA) induced lesioning of midbrain DA neurons. Adult Fischer 344 rats were anesthetized and injected with BMP7 or vehicle into the left substantia nigra, followed by local administration of 9 microg of 6-OHDA into the left medial forebrain bundle. The lesioned animals that received BMP7 pretreatment, as compared to vehicle/6-OHDA controls, had a significant reduction in methamphetamine-induced rotation 1 month after the surgery. BMP7-pretreatment partially preserved KCl-induced dopamine release in the lesioned striatum and significantly increased TH immunoreactivity in the lesioned nigra and striatum. In summary, our data suggest that BMP7 has neuroprotective and/or neuroreparative effects against 6-OHDA lesioning of the nigrostriatal DA pathway in an animal model of Parkinson's disease (PD).

Borlongan CV, Emerich DF, Hoffer BJ, Bartus RT. · Cellular Neurobiology Branch, NIH/NIDA/IRP, 5500 Nathan Shock Drive, 21224, Baltimore, MD, USA · Brain Res. · Pubmed #12445688 No free full text.

Abstract: Cyclosporine-A (CsA) is neuroprotective in animal models of Parkinson's disease (PD), Huntington's disease and stroke. Because CsA does not easily cross the blood-brain barrier (BBB), high doses (i.e. >10 mg/kg in rats) and chronic administration may be necessary to produce beneficial effects. However, immunosuppressant side effects (including nephrotoxicity and hepatotoxicity) are associated with such CsA dosing regimens. The bradykinin B2 receptor agonist, Cereport (labradimil and formerly called RMP-7), transiently increases the permeability of the BBB to facilitate delivery of drugs to the CNS. Here we examined the effects of co-administration of CsA and Cereport in the unilateral 6-OHDA model of PD. Animals were pretreated with vehicle, CsA alone (1 mg/kg, a low dose without either immunosuppressive or neuroprotective effects, or 10 mg/kg, a high dose that produces both immunosuppression and neuroprotection), or CsA (1 mg/kg) in combination with Cereport (9 microg/kg). Behavioral analyses, using elevated body swing and amphetamine-induced rotational tests, revealed that a low dose of CsA was neuroprotective when combined with Cereport, but not when given alone. Tyrosine hydroxylase immunohistochemistry demonstrated that while near complete (>90%) depletions of nigral TH-ir neurons were noted in lesioned animals that received vehicle infusion or low-dose CsA alone, lesioned animals that received low-dose CsA+Cereport exhibited a significant sparing of nigral TH-ir neurons and a marked reduction in the loss of striatal TH-ir fibers. The safer and effective administration of lower doses of CsA combined with enhanced BBB permeability using Cereport, offers a novel way of producing protective effects in the CNS without the toxic liabilities of high-dose CsA.

Chen MT, Morales M, Woodward DJ, Hoffer BJ, Janak PH. · Intramural Research Program, Cellular Neurobiology Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA. · Exp Neurol. · Pubmed #11520122 No free full text.

Abstract: The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving animal; this model should prove useful for testing the behavioral and functional effects of experimental manipulations designed to reduce or reverse the effects of dopaminergic cell loss. In addition, these results suggest that the contralateral changes in striatal function which occur in the unilateral dopaminergic lesion model should be considered when evaluating experimental results.

Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y. · Department of Physiology, National Defense Medical Center, Taipei, Taiwan. · Brain Res. · Pubmed #11516412 No free full text.

Abstract: Previous reports have demonstrated that exogeneous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ventral mesencephalic (VM) dopaminergic (DA) neuron damage induced by 6-hydroxydopamine (6-OHDA) lesioning in rats. Recent studies have shown that 1,25-dihydroxyvitamin D(3) (D3) enhances endogenous GDNF expression in vitro and in vivo. The purpose of present study was to investigate if administration of D3 in vivo and in vitro would protect against 6-OHDA-induced DA neuron injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for 8 days and then lesioned unilaterally with 6-OHDA into the medial forebrain bundle. Locomotor activity was measured using automated activity chambers. We found that unilateral 6-OHDA lesioning reduced locomotor activity in saline-pretreated animals. Pretreatment with D3 for 8 days significantly restored locomotor activity in the lesioned animals. All animals were sacrificed for neurochemical analysis 6 weeks after lesioning. We found that 6-OHDA administration significantly reduced dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanilic acid (HVA) levels in the substantia nigra (SN) on the lesioned side in the saline-treated rats. D3 pretreatment protected against 6-OHDA-mediated depletion of DA and its metabolites in SN. Using primary cultures obtained from the VM of rat embryos, we found that 6-OHDA or H(2)O(2) alone caused significant cell death. Pretreatment with D3 (10(-10) M) protected VM neurons against 6-OHDA- or H(2)O(2)-induced cell death in vitro. Taken together, our data indicate that D3 pretreatment attenuates the hypokinesia and DA neuronal toxicity induced by 6-OHDA. Since both H(2)O(2) and 6-OHDA may injure cells via free radical and reactive oxygen species, the neuroprotection seen here may operate via a reversal of such a toxic mechanism.

Chiang Y, Morales M, Zhou FC, Borlongan C, Hoffer BJ, Wang Y. · Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. · Brain Res. · Pubmed #11166704 No free full text.

Abstract: We have previously demonstrated that intranigral transplantation of fetal ventral mesencephalic (VM) tissue and nigrostriatal administration of glial cell line-derived neurotrophic factor (GDNF) restores striatal dopamine input in hemiparkinsonian rats. Since it has been found that GDNF is highly expressed in fetal kidney, we examined the possibility that fetal kidney tissue may provide trophic support, similar to GDNF, to an intranigral dopamine (DA) transplant and restore the nigrostriatal pathway. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Completeness of the lesion was evaluated by measuring amphetamine-induced rotation. One month after 6-OHDA lesioning, fetal VM cells were grafted into the lesioned nigral area followed by transplantation of fetal kidney tissue or vehicle along a pathway from nigra to striatum. Animals receiving these transplants showed a significant decrease both in amphetamine-induced rotation and in postural asymmetry 1 to 3 months after grafting. Immunocytochemical studies demonstrated tyrosine hydroxylase (TH) positive fiber tracts in the lesioned striatum. Control animals that received vehicle injection after the intranigral graft or no transplantation showed no alterations in amphetamine-induced turning and no TH-positive fibers in the lesioned striatum. These results indicate that combinations of fetal nigral and kidney transplants may restore the nigrostriatal DA pathway in Parkinsonian rats. As fetal kidney contains a variety of trophic proteins, it may provide a synergistic admixture to optimally promote DA fiber outgrowth.