Abstract
Diabetic neuropathy (DN) is a common complication of diabetes mellitus resulting in cognitive dysfunction and synaptic plasticity impairment. Hyperglycemia plays a critical role in the development and progression of DN, through a number of mechanisms including increased oxidative stress. Cannabinoids are a diverse family of compounds which can act as antioxidative agents and exhibit neuroprotective properties. We investigated the effect of the synthetic cannabinoid HU-210 on brain function of streptozotocin (STZ)-induced diabetic mice. These animals exhibit hyperglycemia, increased cerebral oxidative stress and impaired brain function. HU-210, through a receptor independent pathway, alleviates the oxidative damage and cognitive impairment without affecting glycemic control. To study the neuroprotective mechanism(s) involved, we cultured PC12 cells under hyperglycemic conditions. Hyperglycemia enhanced oxidative stress and cellular injuries were all counteracted by HU-210—in a dose dependent manner. These results suggest cannabinoids might have a therapeutic role in the management of the neurological complications of diabetes.
doi:10.1016/S1567-5769(01)00003-0 
Copyright © 2001 Elsevier Science B.V. All rights reserved.Examination of the immunosuppressive effect of Δ9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes*1
Xinguang Li , Norbert E. Kaminski 
, 
and Lawrence J. Fischer
Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, 315 National Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824, USA
Received 19 September 2000; Revised 24 October 2000; accepted 20 November 2000. Available online 7 March 2001.
Abstract
Δ9-Tetrahydrocannabinol (Δ9-THC) is capable of modulating a variety of immune responses, but has not been evaluated in models of immune-based diabetes. The objectives of the present study were: (a) to investigate the effect of Δ9-THC in an established model of multiple low dose streptozotocin (MLDSTZ)-induced autoimmune diabetes; and (b) to determine the contribution of the immune response in the MLDSTZ model. CD-1 mice were treated with 40 mg/kg STZ for 5 days in the presence or absence of Δ9-THC treatment. Δ9-THC administered orally in corn oil at 150 mg/kg for 11 days attenuated, in a transient manner, the MLDSTZ-induced elevation in serum glucose and loss of pancreatic insulin. MLDSTZ-induced insulitis and increases in IFN-γ, TNFα and IL-12 mRNA expression were all reduced on Day 11 by co-administration of Δ9-THC. In separate studies, six doses of Δ9-THC, given after completion of STZ treatment, was found equally effective in attenuating mice from MLDSTZ-induced diabetes. Studies performed using B6C3F1 mice showed moderate hyperglycemia and a significant reduction in pancreatic insulin by MLDSTZ in the absence of insulitis. In addition, MLDSTZ produced a less pronounced hyperglycemia compared to CD-1 mice that was not attenuated by Δ9-THC. These results suggest that MLDSTZ can initiate direct β-cell damage, thereby augmenting the destruction of β-cells by the immune system. Moreover, these results indicate that Δ9-THC is capable of attenuating the severity of the autoimmune response in this experimental model of autoimmune diabetes.
Author Keywords: Author Keywords: Δ9-THC; Diabetes; Streptozotocin
Δ9-THC, Δ9-tetrahydrocannabinol; STZ, streptozotocin; MLDSTZ, multiple low dose streptozotocin; THl, T helper 1 cell; TH2, T helper 2 cell; IFN-γ, interferon-γ; IL-12, interleukin-12; IL-2, interleukin-2; IL-4, interleukin-4; TNFα, tumor necrosis factor α; mAb, monoclonal antibody; RIA, radioimmunoassay; RT-PCR, reverse transcriptase-polymerase chain reaction; NA, naive; VH, vehicle; IS, internal standard; H&E, haematoxylin and eosin; scid, severe combined immunodeficient
