On-Demand Control of the Photochromic Properties of Naphthopyrans.

Photofunctional compounds have emerged as critically important materials for both fundamental studies and industrial applications. Control of the thermal decoloration speed to within several seconds while sustaining satisfactory photochromic colorability is an important challenge for the application of such materials to photochromic lenses and smart windows. Photochromic naphthopyran derivatives are utilized for photochromic lenses because of their high durability and easily controllable colorability. However, the residual color imparted by the long-lived transient species upon ceasing light irradiation remains a hindrance to practical applications. In this study, a strategy is demonstrated for on-demand control of the thermal decoloration speed of the transient colored species of naphthopyran derivatives. The increase in the ring-size of the alkylenedioxy moiety on the naphthopyrans accelerates the thermal back-reaction independently of the maximum-absorption wavelength of the colored isomer, leading to the realization of yellow-, red-, and blue-photochromic naphthopyrans with similar thermal fading speeds. This novel molecular design provides a strategy for the future development of advanced photoresponsive materials.

Neuropharmacological approach against MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. PD is well known to be a chronic and progressive neurodegenerative disease produced by a selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. The main clinical features of PD include tremor, bradykinesia, rigidity and postural instability. Most insights into pathogenesis of PD come from investigations performed in experimental models of PD, especially those produced by neurotoxins. The biochemical and cellular alterations that occur after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) treatment are remarkably similar to that observed in idiopathic PD. Furthermore, it is well known that acute treatment with MPTP can cause a severe loss of tyrosine hydroxylase and dopamine transporter protein levels and dopamine contents in the striatum of mice, as compared to continuous MPTP treatment. Thus these findings may support the validity of acute MPTP treatment model for unraveling in the neurodegenerative processes in PD. In this review, we discuss the neuroprotective effects of various compounds against neuronal cell loss in an MPTP model of PD. This review may lead to a much better understanding of PD as well as provide novel clues to new targets for therapeutic interventions in PD patients.

Role of glial cells in neurotoxin-induced animal models of Parkinson's disease.

Dopaminergic neurons are selectively vulnerable to oxidative stress and inflammatory attack. The neuronal cell loss in the substantia nigra is associated with a glial response composed markedly of activated microglia and, to a lesser extent, of reactive astrocytes although these glial responses may be the source of neurotrophic factors and can protect against oxidative stress such as reactive oxygen species and reactive nitrogen species. However, the glial response can also mediate a variety of deleterious events related to the production of pro-inflammatory, pro-oxidant reactive species, prostaglandins, cytokines, and so on. In this review, we discuss the possible protective and deleterious effects of glial cells in the neurodegenerative diseases and examine how these factors may contribute to the pathogenesis of Parkinson's disease. This review suggests that further investigation concerning glial reaction in Parkinson's disease may lead to disease-modifying therapeutic approaches and may contribute to the pathogenesis of this disease.

Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) neurotoxicity in mice.

We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.

Biochemical alterations of the striatum in an MPTP-treated mouse model of Parkinson's disease.

We investigated the biochemical alterations of the striatum of mice subjected to seven experimental schedules with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment. The mice were treated intraperitoneally (i.p.) with MPTP (20 mg/kg in saline) four times a day at 2-hr intervals showed severe and persistent depletions of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, as compared with those (1) treated with MPTP (15 mg/kg in saline, i.p.) once a day for 14 consecutive days; (2)MPTP (30 mg/kg in saline, i.p.) twice a day for 5 consecutive days; (3) MPTP (10 mg/kg in saline, i.p.) four times a day at 1-hr intervals for 2 consecutive days; (4) MPTP (20 mg/kg in saline, i.p.) once a day for 4 consecutive days; (5) MPTP (20 mg/kg in saline, i.p.) twice a day for 2 consecutive days; (6) MPTP (20 mg/kg in saline, i.p.) twice a day for 4 consecutive days. In our Western blot analysis, furthermore, the mice that received MPTP (20 mg/kg in saline) four times a day at 2-hr intervals showed a severe decrease of the striatal tyrosine hydroxylase (TH) protein levels and a significant increase of the striatal glial fibrillary acidic protein (GFAP) levels. These results demonstrate that the model with acute MPTP treatment can cause severe neuronal damage in the mouse striatum, as compared to the model with continuous treatment with MPTP. Thus our findings may support the validity of acute MPTP treatment model for unraveling in the neurodegenerative processes in PD.

Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice.

We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.

Poly(ADP-ribose)polymerase inhibitor can attenuate the neuronal death after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice.

An excessive expression of poly(ADP-ribose)polymerase (PARP) has been demonstrated to play a key role in the pathogenesis of Parkinson's disease (PD). Here we investigated the therapeutic effect of the PARP inhibitor benzamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. In our HPLC and Western blot analysis, pretreatment with benzamide showed a neuroprotective effect against MPTP neurotoxicity in mice. Posttreatment with benzamide also attenuated MPTP neurotoxicity in mice. Furthermore, our immunohistochemical study showed that posttreatment with benzamide significantly prevented neuronal damage by suppressing overexpression of neuronal, microglial, and astroglial PARP after MPTP treatment. These findings have important implications for the therapeutic time window and choice of PARP inhibitors in PD patients. Our present findings provide further evidence that PARP inhibitor may offer a novel therapeutic strategy for PD.

Systemic administration of proteasome inhibitor protects against MPTP neurotoxicity in mice.

Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L: -gamma-t-butyl-L: -glutamyl-L: -alanyl-L: -leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.

A novel anti-Parkinsonian agent, zonisamide, attenuates MPTP-induced neurotoxicity in mice.

Zonisamide, an anti-convulsant drug, has recently been shown to exert beneficial effects in Parkinson's disease (PD). However, actual pathophysiological mechanism underlying the anti-parkinsonian effect of zonisamide remains uncertain. Here we tested exactly the neuroprotective effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. We observed that zonisamide attenuated MPTP-induced dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) depletion in the striatum and reduced the loss of tyrosine hidroxylase (TH) positive neurons and the increase of glial fibrillary acidic protein (GFAP) positive astrocytes in the striatum and substantia nigra after 5 days. Our Western blot analysis study also showed that zonisamide can prevent the decrease of TH protein levels and increase of GFAP protein levels in the striatum 5 days after MPTP treatment. In the present study, on the other hand, zonisaimde treatment showed no significant changes of the striatal dopamine, DOPAC, and HVA content in the striatum of normal mice after 1 day, as compared to the vehicle-treated group. Furthermore, zonisamide produced a significant increase of the TH protein levels in the striatum after 1 day, as compared to vehicle-treated group. In contrast, zonisamide showed no significant changes of the GFAP protein levels in the striatum after 1 day, as compared to vehicle-treated group. These results show that anticonvulsant drug, zonisamide, has the neuroprotective effect in the MPTP model of PD in mice. Our study also demonstrates that the neuroprotective effect of zonisamide against dopaminergic cell damage may be mediated by the elevation of TH activity on dopaminergic system after MPTP treatment in mice. Our findings suggest that zonisamide may offer a new approach for the treatment of PD.

Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson's disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder after Alzheimer's disease. The main clinical features of PD include tremor, bradykinesia, rigidity and postural instability. The primary pathology of PD is degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in loss of the nigrostriatal pathway and a reduction of dopamine contents in the striatum. The biochemical and cellular changes that occur following the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are remarkably similar to that seen in idiopathic PD. Recent evidence shows that oxidative stress contributes to the cascade leading to dopaminergic cell degeneration in PD. However, oxidative stress is intimately linked to other components of neurodegenerative process, such as nitric oxide stress and inflammation. Recently, there is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. In view of these new insights, however, the role of reactive nitrogen species, reactive oxygen species and inflammation against MPTP neurotoxicity is not fully understood. In this review, we discuss the possible role of reactive nitrogen species, reactive oxygen species and inflammation in the dopaminergic neurons against MPTP neurotoxicity.