Brain‐Derived Neurotrophic Factor, Neurotrophin‐3, and Neurotrophin‐4/5 Prevent the Death of Striatal Projection Neurons in a Rodent Model of Huntington's Disease

Abstract

Intrastriatal injection of quinolinate has been proven to be a very useful animal model to study the pathogenesis and treatment of Huntington's disease. To determine whether growth factors of the neurotrophin family are able to prevent the degeneration of striatal projection neurons, cell lines expressing brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) were grafted in the adult rat striatum before quinolinate injection. Three days after lesioning, ongoing cell death was assessed by in situ detection of DNA fragmentation. In animals grafted with the control cell line, quinolinate injection induced a gradual cell loss that was differentially prevented by intrastriatal grafting of BDNF-, NT-3-, or NT-4/5-secreting cells. Seven days after lesioning, we characterized striatal projection neurons that were protected by neurotrophins. Quinolinate injection, alone or in combination with the control cell line, induced a selective loss of striatal projection neurons. Grafting of a BDNF-secreting cell line prevented the loss of all types of striatal projection neurons analyzed. Glutamic acid decarboxylase 67-, preproenkephalin-, and preprotachykinin A-but not prodynorphinexpressing neurons were protected by grafting of NT-3-or NT-4/5-secreting cells but with less efficiency than the BDNF-secreting cells. Our findings show that neurotrophins are able to promote the survival of striatal projection neurons in vivo and suggest that BDNF might be beneficial for the treatment of striatonigral degenerative disorders, including Huntington's disease. Key Words: Rat striatum-Quinolinate-Grafting-Survival. J. Neurochem. 75, 2190 -2199 (2000).Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene (MacDonald and Gusella, 1996;Mangiarini et al., 1996). Its predominant pathological feature is a massive and progressive degeneration of striatal output neurons without substantial loss of striatal interneurons and afferents (for review, see DiFiglia, 1990). Intrastriatal injection of quinolinate (QUIN), an NMDA receptor agonist, replicates many neurochemical, histological, and behavioral features of HD (Beal et al., 1986;DiFiglia, 1990). Striatal projection neurons containing enkephalin are affected to a greater extent than substance P-containing neurons, and those neurons surviving the lesion express reduced levels of their mRNAs both in HD (Reiner et al., 1988;Richfield et al., 1995) and after QUIN injections (Pérez-Navarro et al., 1999a,b). Excitotoxicity and apoptosis have been suggested to be involved in the degeneration of neurons in HD (Thomas et al., 1995;Petersén et al., 1999) and after QUIN injection (Ferrer et al., 1995;Portera-Cailliau et al., 1995;Hughes et al., 1996). Furthermore, intrastriatal QUIN injections have been found to induce huntingtin mRNA (Carlock et al., 1995) and protein (Tatter et al., 1995), providing a possible link between the QUIN model and HD.Members of the neurotr...

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

“…39,40 Neuroprotective strategies using several growth factors have also been proposed for HD. [41][42][43] Among them, BDNF, so far the best candidate, has been shown to modulate the onset and severity of motor and cognitive functions in HD mouse models 5,18,19,44 and to participate in the disruption of the cortico-striatal glutamatergic transmission that occurs in HD. 45,46 Furthermore, transgenic mice overexpressing BDNF in the cerebral cortex, when cross-mated with R6/1 Conditional release of BDNF in Huntington's disease A Giralt et al mice, improve several morphological and behavioral symptoms.…”

“…29 We have previously shown that BDNF-overexpressing cell lines prevent the death of striatal projecting neurons in a rat model of HD. 43 However, the methodology used in these studies cannot be used for chronic pathologies because of the likelihood of tumor generation by brainimplanted fibroblasts. 47 The use of stem cells in HD cell therapy has also emerged as a powerful tool for the release of striatal neuron protecting neurotrophic factors.…”

“…Although BDNF has a clear survival effect on striatal neurons, 6,43 we cannot rule out that the upregulated BDNF levels produced by pGFAP-BDNF-grafted astrocytes induced synergistic effects with other released molecules during inflammation and thereby exert more neuroprotection. 34 However, it is noteworthy that BDNF also increases neurogenesis in QUIN-lesioned striatum, 55 and the induction of neostriatal neurogenesis produces a functional improvement in R6/2 mice.…”

Cell therapy in Huntington disease

“…Neural stem cells are responsive to BDNF, 20,33 and BDNF itself participates in cell differentiation. 112,153 Cortically derived BDNF is an important survival molecule for striatal projection neurons, 123,144 and BDNF is responsive to lesioning of the rodent striatum. 16,26 Reductions in cortical BDNF mRNA 164 and defective transport 60 underlie decreased striatal BDNF and correlate with HD progression in a transgenic mouse model of HD 164,165 and brain tissue in humans with HD.…”

AAV–BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment

“…While the molecular mechanisms by which an expanded polyglutamine tract leads to the selective loss of striatal neurons in HD patients is still to be fully elucidated, attention has been given to endogenously expressed neurotrophic factors known to play a critical role in the development and maintenance of the nervous system, including brain-derived neurotrophic factor (BDNF), [1][2][3][4] glial-derived neurotrophic factor 1,[5][6][7] and ciliary neurotrophic factor [8][9][10][11][12] to provide a broad approach to attenuate neurodegenerative processes.…”