Chemokines in the MPTP model of Parkinson's disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration

Recent studies have invoked inflammation as a major contributor to the pathogenesis of Parkinson's disease (PD). We determined the role of members of the chemokine system, key inflammatory mediators, in PD pathogenesis. In the MPTP model of murine PD, several chemokines, including CC chemokine ligand 2 (CCL2, Monocyte Chemoattractant Protein-1) and CCL3 (Macrophage Inflammatory Protein-1alpha), were upregulated in the striatum and the ventral midbrain. Astrocytes were the predominant source of CCL2 and CCL3 in the striatum and the substantia nigra, and dopaminergic neurons in the substantia nigra constitutively expressed these two chemokines. MPTP treatment resulted in decreased CCL2 expression and increased CCL3 expression in the surviving dopaminergic neurons. Because we found that CCL2 induced production of TNF-alpha in microglial cells, a cytokine known to play a detrimental role in PD, we anticipated that deletion of the genes encoding CCL2 and CCR2, its major receptor, would confer a protective phenotype. However, MPTP-induced striatal dopamine depletion was comparable in double knockout and wild-type mice. Our results demonstrate that chemokines such as CCL2 are induced following MPTP treatment, but that at least within the context of this PD model, the absence of CCL2 and CCR2 does not protect against striatal dopamine loss.     

Constitutive neuronal expression of CCR2 chemokine receptor and its colocalization with neurotransmitters in normal rat brain: functional effect of MCP-1/CCL2 on calcium mobilization in primary cultured neurons

Chemokines and their receptors are well described in the immune system, where they promote cell migration and activation. In the central nervous system, chemokine has been implicated in neuroinflammatory processes. However, an increasing number of evidence suggests that they have regulatory functions in the normal nervous system, where they could participate in cell communication. In this work, using a semiquantitative immunohistochemistry approach, we provide the first neuroanatomical mapping of constitutive neuronal CCR2 localization. Neuronal expression of CCR2 was observed in the anterior olfactory nucleus, cerebral cortex, hippocampal formation, caudate putamen, globus pallidus, supraoptic and paraventricular hypothalamic nuclei, amygdala, substantia nigra, ventral tegmental area, and in the brainstem and cerebellum. These data are largely in accordance with results obtained using quantitative autoradiography with [(125)I]MCP-1/CCL2 and RT-PCR CCR2 mRNA analysis. Furthermore, using dual fluorescent immunohistochemistry we studied the chemical phenotype of labeled neurons and demonstrated the coexistence of CCR2 with classical neurotransmitters. Indeed, localization of CCR2 immunostaining is observed in dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area as well as in cholinergic neurons in the substantia innominata and caudate putamen. Finally, we show that the preferential CCR2 ligand, MCP-1/CCL2, elicits Ca(2+) transients in primary cultured neurons from various rat brain regions including the cortex, hippocampus, hypothalamus, and mesencephalon. In conclusion, the constitutive neuronal CCR2 expression in selective brain structures suggests that this receptor could be involved in neuronal communication and possibly associated with cholinergic and dopaminergic neurotransmission and related disorders.     

Degeneration of nigrostriatal dopaminergic neurons in an experimental model of the early clinical stage of Parkinson’s disease

The basis of the pathogenesis of Parkinson’s disease (PD) is progressive degeneration of dopaminergic neurons in the nigrostriatal system of the brain. The most important treatment of PD is using of drugs that delay neuronal death. The aim of the present study was to adapt our model of the early clinical stage of PD in mice [1] for its use as a test system for trials of potential neuroprotectors. Our data show that degeneration of the bodies of dopaminergic neurons in the substantia nigra starts 3 h after the last injection of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) whereas the number of dopaminergic axons in the striatum is significantly decreased by this time point. Degradation of axons and neuronal bodies continues for the next 3 h. This period of time appears to be more appropriate for testing of neuroprotectors because later the number of neuronal bodies in the substantia nigra and axons in the striatum do not change. For the development of the test system, it is important to evaluate the functional state of surviving neurons. We found that 3 h after the last MPTP injection, the dopamine (DA) content in the substantia nigra decreased to 25% of the control level and 24 h later the DA content increased again and was 70% of the control value. The tyrosine hydroxylase content in neuronal bodies was similar to the control during the entire period of the study. In the striatum, the DA level decreased to 90% 3 h after the last MPTP injection and remained unchanged by the end of the study; however, the content of tyrosine hydroxylase decreased gradually by 12 h after the injection. Our data probably show the compensatory activation of tyrosine hydroxylase in both the substantia nigra and striatum. Thus, in a mouse model of the early clinical stage of PD we revealed that degeneration of nigrostriatal dopaminergic neurons ends 14 h after the start of the action of the specific neurotoxin. This was accompanied by activation of compensatory processes, which enhance DA-ergic neurotransmission.     

鱼藤酮致大鼠脑内α-突触核蛋白的表达分布变化

目的 研究鱼藤酮所致的帕金森病大鼠的脑内α-突触核蛋白（α—synuclein,ASN）分布。方法 Wistar大鼠随机分成两组,分别给予鱼藤酮和／或溶剂（对照组）皮下注射,4周后取脑组织,对黑质部位HE染色,光镜下观察Lewy小体形态;对黑质、海马、纹状体等脑区进行酪氨酸羟化酶（tyrosine hydroxylase,TH）、ASN免疫组织化学染色。结果 在对照组大鼠脑内,ASN广泛分布于各脑区,尤其在皮质、纹状体、海马等纤维投射丰富的区域。鱼藤酮处理的大鼠脑中,黑质TH阳性多巴胺能神经元数目减少、纹状体区TH阳性纤维脱失,黑质部位可见Lewy小体样结构;ASN阳性染色在各个脑区均有增强但各个脑区增强程度不一,黑质部位神经元胞浆和胞核内均有ASN明显聚集,纹状体可见ASN聚集围绕在细胞周围。海马部位偶见ASN在胞浆中点状聚集,胞核中无明显改变。结论 在鱼藤酮皮下注射导致的帕金森病大鼠的脑内,ASN在多个脑区中表达增加,而在黑质纹状体部位聚集最为明显,蛋白分布由多巴胺能神经元的突触末端向胞浆和胞核扩展。     

Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease

Background

Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.

Objective

To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.

Methods

Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively.

Results

Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load.

Conclusions

In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Transplantation of neural stem cells co-transfected with Nurr1 and Brn4 for treatment of Parkinsonian rats

Neural stem cells (NSCs) tranplantation has great potential for the treatment of neurodegenerative disease such as Parkinson's disease (PD). However, the usage of NSCs is limited because the differentiation of NSCs into specific dopaminergic neurons has proven difficult. We have recently demonstrated that transgenic expression of Nurr1 could induce the differentiation of NSCs into tyrosine hydroxylase (TH) immunoreactive dopaminergic neurons, and forced co-expression of Nurr1 with Brn4 caused a dramatic increase in morphological and phenotypical maturity of these neurons. In this study, we investigated the effect of transplanted NSCs in PD model rats. The results showed that overexpression of Nurr1 promoted NSCs to differentiate into dopaminergic neurons in vivo, increased the level of dopamine (DA) neurotransmitter in the striatum, resulting in behavioral improvement of PD rats. Importantly, co-expression of Nurr1 and Brn4 in NSCs significantly increased the maturity and viability of dopaminergic neurons, further raised the DA amount in the striatum and reversed the behavioral deficit of the PD rats. Our findings provide a new potential and strategy for the use of NSCs in cell replacement therapy for PD.     

Neuroprotective effects of delayed administration of growth/differentiation factor-5 in the partial lesion model of Parkinson's disease

Neurotrophic factors have the potential for therapeutic use in Parkinson's disease (PD) to support the remaining dopaminergic neurons and protect them against the ongoing disease process. We have examined the effects of the neurotrophin growth and differentiation factor-5 (GDF-5) in a rat model of Parkinson's disease, the intrastriatal 6-hydroxydopamine (6-OHDA) lesion. GDF-5 (25 microg) was injected into either the striatum or substantia nigra (SN) of adult rats at 1 or 2 weeks after 6-hydroxydopamine administration. The behavioral effects of GDF-5 treatment were examined in vivo by amphetamine-induced rotational testing. Injection of GDF-5 into the nigra at either 1 or 2 weeks, or into the striatum at 1 week, after the lesion induced significant decreases in rotations. Post-mortem immunocytochemistry after 6 weeks showed that GDF-5 administration into either site protected dopaminergic cell bodies of the nigra when injected at 1 but not 2 weeks after 6-hydroxydopamine. However, no significant protection of striatal dopaminergic fiber density was observed after GDF-5 treatment. This study shows that the delayed administration of a single dose of GDF-5 has significant protective effects on the damaged adult rat nigrostriatal pathway, reinforcing its therapeutic potential for Parkinson's disease.     

A potential target for the treatment of Parkinson's disease: Effect of lateral habenula lesions

ObjectiveParkinson's disease (PD) is a progressive neurodegenerative movement disorder that is caused predominantly by the degeneration of the nigrostriatal dopaminergic pathway. Lateral habenula (LHb) has efferent projections that terminate in the substantia nigra pars compacta (SNpc) and electrical stimulation of the LHb effectively suppresses the activity of dopamine-containing neurons in the SNpc. This study was aimed to investigate whether LHb lesions can ameliorate the syndromes of PD via affecting the activities of SNpc neurons in 6-hydroxydopamine (6-OHDA)-induced PD model rats.MethodsConcentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, which is the area projected by the SNpc dopaminergic neurons were assayed by high-performance liquid chromatography (HPLC) coupled with fluorescence detection. The immunohistochemical method was applied to detect the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra.ResultsThe results showed that LHb lesions induced a significant reduction in apomorphine-induced rotational behavior. The DA, DOPAC and HVA levels in the striatum of PD model rats were increased by the LHb lesions.ConclusionTherefore, we speculate that the LHb lesions induced a significant amelioration in motor disorders via increasing the DA levels in the striatum, which may lead to a potential therapeutic strategy for the treatment of PD.     

Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft

The current transplantation strategy in experimental and clinical Parkinson's disease (PD) has been to place nigral dopaminergic grafts not in their ontogenic site (substantia nigra) but in their target area (striatum). Although intrastriatal dopaminergic grafts are capable of reinnervating the striatum, they fail to reinnervate the nigra, which may be an important factor limiting the efficacy of fetal tissue transplantation in parkinsonian patients. We have previously shown that simultaneous intrastriatal and intranigral dopaminergic grafts (double grafts) may provide a more complete restoration of the nigrostriatal circuitry (Mendez et al. [1996] J Neurosci 16:7216-7227; Mendez and Hong [1997] Brain Res 778:194-205). In the present study, we investigated the contribution of the intranigral graft to functional recovery in double-grafted hemiparkinsonian rats. Twenty Wistar rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were divided into two groups and received either double grafts (n = 10) or intrastriatal grafts alone (n = 10). Following transplantation, both intrastriatally and double-grafted animals had a significant decrease in rotational behavior. However, only animals with double grafts exhibited a significant increase in contralateral adjusting step performance. The intranigral graft was subsequently lesioned by a second 6-OHDA injection. Following the second lesion, animals with double grafts exhibited a significant reversal of rotational behavior and a 51% reduction in contralateral adjusting step performance. The reversal in functional recovery correlated with a significant loss of intranigral grafted neurons. These results suggest that the intranigral graft has an important role in the functional recovery of double-grafted animals. Restoration of dopaminergic innervation to both the nigra and the striatum may be crucial for optimizing graft efficacy and may be a superior strategy in neural transplantation for PD.     

Embryonic substantia nigra grafts innervate embryonic striatal co-grafts in preference to mature host striatum

Embryonic substantia nigra grafts partially reinnervate the dopamine-denervated corpus striatum when implanted adjacent to that structure. This reinnervation is generally limited to a small portion of the denervated striatum and does not completely compensate for the behavioral effects of a 6-hydroxydopamine lesion of the substantia nigra. This limited reinnervation may be due to the fact that adult denervated striatum is not an ideal target for dopaminergic neurites. To test this hypothesis, embryonic striatum and embryonic substantia nigra were implanted together into the lateral ventricle of adult rats, adjacent to the denervated striatum. Five months after transplantation, fluorescence histochemistry showed that the embryonic striatal grafts were exclusively reinnervated with little or no reinnervation of the adult host striatum. When substantia nigra was implanted without embryonic striatal co-grafts, reinnervation of the host striatum was observed. We conclude that embryonic striatum is a better target tissue than adult denervated striatum for developing dopaminergic neurites and hypothesize that this difference may be due to the presence or the absence of specific trophic factors.     

Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease

Parkinson's disease (PD) is a brain degenerative disorder with unknown etiology, and specific degeneration of mesencephalic dopaminergic cells is a morphological manifestation of the disease. The central histaminergic system appears to be activated in PD, since the histaminergic innervation is increased in the substantia nigra. The aim of the present study was to investigate the expression and function of histamine H(3) receptors in PD, using receptor mRNA in situ hybridization with oligonucleotide probes, receptor binding assay with a specific radioactive agonist, and GTP-gamma-[(35)S]-binding assay as a tool to study the activation of the receptor G-protein. H(3) receptor binding sites were detected using N-alpha-methylhistamine autoradiography in the basal ganglia and cortex, being most abundant in the substantia nigra and striatum. In PD substantia nigra we detected an increase of the receptor binding density. In situ hybridization study of the receptor mRNA revealed prominent sites of H(3) receptor synthesis in the putamen, cortex, and globus pallidus, whereas very low mRNA expression was seen in the substantia nigra. In the PD pallidum externum, H(3) receptor mRNA expression was elevated as compared with the normal brains. GTP-gamma-[(35)S]-binding assay did not reveal any significant difference between PD and normal brains, although the density values in PD substantia nigra tended to be lower than in the normal brain, and density values in PD striatum were higher. The dopaminergic neurons did not express significant amount of H(3) receptor mRNA, suggesting that the effects of H(3) receptor-mediated modulation of dopamine release are indirect. Our data indicates modulation of the histamine H(3) receptor in PD at the level of the mRNA expression in the striatum and receptor density in the substantia nigra. The receptor activity seems to be unchanged or decreased, as revealed by GTP-gamma-[(35)S]-binding assay. Modulation of the histamine H(3) receptor may influence the activity of other neurotransmitter systems, e.g., the GABAergic one, in the substantia nigra.     

Gene therapy of Parkinson's disease using adeno-associated virus (AAV) vectors

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of dopamine-synthesizing enzymes [tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)]. The most appropriate gene-delivery vehicles for neurons are adeno-associated virus (AAV) vectors, which are derived from non-pathogenic virus. Therefore, TH and AADC genes were introduced into the striatum in the lesioned side using separate AAV vectors in parkinsonian rats, and the coexpression of TH and AADC resulted in better behavioral recovery compared with TH alone. Another strategy for gene therapy of PD is the protection of dopaminergic neurons in the substantia nigra using an AAV vector containing a glial cell line-derived neurotrophic factor (GDNF) gene. Combination of dopamine-supplement gene therapy and GDNF gene therapy would be a logical approach to the treatment of PD.     

Dopaminergic neuroprotection by neurturin-expressing c17.2 neural stem cells in a rat model of Parkinson's disease

Genetically engineered neural stem cell (NSC) lines are promising vectors for the treatment of regenerative diseases, especially Parkinson's disease (PD). Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor-family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. Here, we have generated a NTN-secreting c17.2 NSC line and investigated the protective effect of NTN-c17.2 on PD rat models. These NTN-releasing NSCs engrafted and integrated in the host striatum with good success, gave rise to neurons, astrocytes and oligodendrocytes, and maintained stable, high-level NTN expression. In addition, inverse transfer of NTN protein into the substantia nigra (SN) was able to protect dopaminergic neurons from 6-OHDA toxicity. Observation of rotational behavior showed that the NTN group performed significantly better than the Mock group, and the protective effect of NTN lasted for at least 4 months. HPLC tests indicated that the contents of neurotransmitters (e.g. dopamine) in the corpus striatum area of the NTN-c17.2 group and the Mock-c17.2 group were significantly higher than in the PBS group, but there was no significant difference between expression in the NTN-c17.2 and Mock-c17.2 groups. Taken together, our results suggest that transplantation of NTN-secreting NSCs exerted protective on PD rat models.     

帕金森病模型大鼠黑质多巴胺能神经元的氧化应激研究

目的　探索帕金森病模型大鼠黑质多巴胺能神经元的氧化应激发病机制。方法　通过立体定位仪 ,将 6-OHDA注入大鼠一侧纹状体内制备 PD模型 ,2周后观察动物的行为学改变 ,2个月后观察黑质纹状体等的病理形态学变化 ,检测模型组、假手术组和正常对照组的超氧化物歧化酶 (SOD)的活性 ,丙二醛 (MDA)、一氧化氮(NO)代谢产物 (NO x)的含量的变化。结果　成功 PD模型鼠有 2 2只。光镜下 HE染色示模型组右侧黑质的多巴胺神经元受损 ,数目减少。模型组右侧黑质的 SOD的含量下降 ,MDA及 NO x含量明显升高 ,与左侧、假手术组及正常对照组相比有显著差异 (P>0 .0 5)。结论　 6-OHDA纹状体内双靶点注射法是一种有效的制备 PD模型的方法。帕金森病大鼠模型黑质内 SOD活性下降 ,MDA、NO x含量升高 ,氧化应激在 PD的发病中起重要的作用     

脂多糖对多巴胺能神经元的损毁作用及其机制研究

目的观察脂多糖(1ipopolysaccharide．LPs)对黑质多巴胺(dopamine，DA)能神经元的损毁作用，探讨免疫机制与帕金森病(Parkinsondisease，PD)发病的相关性。方法采用立体定向术将LPS注人大鼠单侧黑质后分别于注射后2、3、4周经腹腔注射阿朴吗啡诱发动物旋转行为；采用高效液相色谱一电化学法(high performanee liquid chromatography，HPLC)测定纹状体和黑质部位DA等单胺类递质含量；采用免疫组化法检测黑质酪氨酸羟化酶(tyrosine hydroxylase，TH)阳性细胞数；采用尼(氏)染色(Nissl)观察小胶质细胞的活化和以双重免疫酶染色法观察小胶质细胞活化和诱导型一氧化氮合酶(inducible nitric oxide，iNOS)合成。结果大鼠单侧黑质注人LPS后2、3、4周，以阿朴吗啡诱发大鼠均出现旋转行为，其损伤侧纹状体和黑质DA及其代谢物含量降低了30%～70%，注射侧的黑质TH阳性细胞数减少，尤以3周和4周为甚．尼(氏)染色和双重免疫酶染色法也分别显示LPS注射侧小胶质细胞活化，同时伴有iNOS合成的增加。结论LPS对DA能神经元具有一定的损毁作用，小胶质细胞的活化及其释放的NO有可能参与该细胞死亡，提示免疫机制与PD的发病可能存在相关性。     

尼古丁对帕金森病大鼠纹状体多巴胺及黑质自由基含量的影响

目的 :研究尼古丁对帕金森病大鼠的影响 ,探讨其对 PD的作用机制。方法 :通过 6 - OHDA脑立体定向注射术建立大鼠帕金森病模型。采用生化方法观察不同剂量尼古丁对帕金森病大鼠的作用 ,检测黑质自由基、抗氧化剂及多巴胺含量的变化。结果 :造模前及造模后皮下注射尼古丁的 PD大鼠 ,黑质自由基及抗自由基酶及多巴胺含量较PD组有明显改善 (P<0 .0 5 )。结论 :尼古丁可减轻 6 - OHDA对黑质 DA能神经元的损伤 ,对 PD大鼠具有保护作用     

Simultaneous intrastriatal and intranigral grafting (double grafts) in the rat model of Parkinson's disease

Experimental and clinical studies of neural transplantation in Parkinson's disease have focused on the placement of fetal dopaminergic grafts not in their ontogenic site (substantia nigra) but in the main nigral target area (striatum). The reason for this is the apparent inability of intranigral nigral grafts to extend axons for long distances reinnervating the ipsilateral striatum. This review presents previous work by our laboratory [I. Mendez, M. Hong, Reconstruction of the striato-nigro-striatal circuitry by simultaneous double dopaminergic grafts: a tracer study using fluorogold and horseradish peroxidase, Brain Res. 778 (1997) 194–205; I. Mendez, D. Sadi, M. Hong., Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants, J. Neurosci. 16 (1996) 7216–7227] using a new transplantation strategy aimed at restoring dopaminergic innervation of the nigra and striatum by simultaneous dopaminergic transplants placed in the substantia nigra and ipsilateral striatum (double grafts) in the 6-hydroxydopamine lesioned adult rat brain. These double grafts achieve not only greater striatal reinnervation than the standard intrastriatal grafts but also produce a faster and more complete behavioural recovery six weeks after transplantation. Injection of the retrograde tracer fluorogold into the striatum and nigra resulted in fluorescent labeled cells within the intranigral graft and the intrastriatal graft and surrounding striatum, respectively suggesting that these double grafts promote at least partial reconstruction of the nigrostriatal dopaminergic pathway. This double graft strategy may have potential implications in clinical neural transplantation for Parkinson's disease.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson''s disease

BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson’s disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein α-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated α-synuclein increased in the same regions. VPA treatment counteracted both these α-synuclein alterations. Furthermore, monoubiquitinated α-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of α-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.