Neuroprotective Strategies in Neural Grafting

互联网2014-02-14

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The survival of neural grafts is dependent on a multitude of both donor-and host-related conditions. The importance of several of these factors, such as anatomical specificity and age of the donor tissue, surgical technique, immunology, presence of growth factors, and so on, are described in other chapters of this book. The significance of obtaining good survival of neural transplants from a limited source of donor tissue is particularly pertinent when transplanting immature dopamine (DA) neurons. Clinical trials with human embryonic nigral grafts in Parkinson’s disease have clearly shown that the implants can provide major symptomatic relief in the patients (Kordower et al., 1996 , Kordower et al., 1998 ; Lindvall, 1997 ; Tabbal et al., 1998 ). The success of this therapy is intimately coupled to a significant restoration of striatal DA levels, as evidenced by positron emission tomography scans, and this can only be achieved when there is good transplant survival. Also, in experimental animals with lesions of the nigrostriatal pathway, a clear correlation between the number of surviving dopaminergic (DA-ergic) neurons in grafts and the degree of behavioral restoration has been found (for review, see Brundin et al., 1994 ). Studies in experimental animals indicate that survival rate of transplanted DA neurons is typically approx 5–15% (Table 1 ). Neuropathological data from two human transplant cases suggest that the survival rate of grafted DA-ergic neurons in Parkinson’s disease patients is in the lower range of this interval (Kordower et al., 1996 ,Kordower et al., 1998 ).

Table 1 Attempts at Enhancing Survival of Grafted Rat DA-ergic Neurons by Different Treatments

	Control (% Survival)	Treatment (% Survival)	Notes
GDNF
Rosenblad et al., 1996^a	9.7	37.4
Sinclair et al., 1996^b	0.7	8.1
Sinclair et al., 1996^a	1.0	13.0
Granholm et al., 1997		2.5-fold increase	No absolute quantification
Apostolides et al., 1997^a	2.4	1.6	Fresh
Apostolides et al., 1997^a	2.6	3.4	Hibernated 6 d
Mehtaetal., 1998^a	1.6	2.0	Hibernated 6 d
Sautter et al., 1998^b	5.1	12.9
Yureketal., 1998^b	1.9	5.8
bFGF
Mayer et al., 1993^a	0.9	1.6	3-wk survival
Mayer et al., 1993^b	1.0	2.7	9-wk survival
Takayama et al., 1995^a	6.3	87.5
Takayama et al., 1995^b	1.5	20.0
Zeng et al., 1996^a	10.9	25.0
GDNF + bFGF + IGF
Zawada et al., 1998	8.2	12.7	24-h survival
Zawada et al., 1998	4.1	6.6	7-d survival
Lazaroids
Nakao et al., 1994^b	15.7	41.4
Grasbon-Frodl et al., 1996^b	^b 6.5	14.0	Hibernated 8 d
Bj�rklund et al., 1997^b	0.9	2.3	Solid grafts in anterior eye chamber
Karlsson et al., 1999^b	6.4	10.9
Calcium antagonists Finger and Dunnett, 1989		Increased graft volume	Dopamine neurons not quantified
Kaminski Schierle et al., 1999^b	8.2	21.5
Caspase inhibitors Schierle et al., 1999^b	10	36

Figures are either those stated by the respective authors or have been computed based on data presented in the publication based on one of the two following assumptions:

^a Approximately 8% of the cells in dissected embryonic rat mesencephalic tissue are DA-ergic. These assumptions imply that there are around 400,000 cells obtained from each dissected ventral mesencephalon.

^b There are approx 35,000 DA neurons in one rat embryonic mesencephalon.