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A quantitative study of the effects of several nucleoside analogues on established herpes encephalitis in mice
Abstract:
Mice with established herpes encephalitis were used to compare the effects of chemotherapy using three different nucleoside analogues. Encephalitis was produced by intranasal inoculation of a type 1 strain of herpes simplex virus. Without chemotherapy all mice died within 5 to 7 days of inoculation. Oral acyclovir (ACV) was a successful preventative measure if commenced within 2 days of inoculation but much less effective if the onset of treatment was further delayed. From the third day, when central nervous system infection had definitely become established, ACV only reduced mortality if given intraperitoneally (i.p.) at regular 6-hourly intervals. Comparison with bromovinyldeoxyuridine (BVdU) and the new nucleoside analogue dihydroxypropoxymethylguanine (DHPG) using the same 6-hourly i.p. regimen revealed that BVdU was poorly effective, despite better activity in vitro, whereas DHPG was the most successful. Virus was rapidly eradicated from all parts of the brain by DHPG therapy, and by day 10, no infectious virus remained in the brains of treated mice, no virus antigens were observed and no trace of virus DNA could be detected in neural tissues by Southern blotting.
Insights
Dihydroxypropoxymethylguanine (DHPG) effectively treated herpes encephalitis in mice, eradicating the virus from the brain. This antiviral nucleoside analogue showed superior efficacy compared to acyclovir and bromovinyldeoxyuridine in established infections.
Area of Science:
- Virology
- Neuroscience
- Pharmacology
Background:
- Herpes simplex virus type 1 (HSV-1) causes herpes encephalitis, a severe neurological condition.
- Established central nervous system infections present significant therapeutic challenges.
- Nucleoside analogues are a key class of antiviral agents.
Purpose of the Study:
- To compare the efficacy of three nucleoside analogues against established herpes encephalitis in a murine model.
- To evaluate the impact of treatment timing on antiviral effectiveness.
- To identify the most potent antiviral agent for established HSV-1 brain infections.
Main Methods:
- Herpes encephalitis was induced in mice via intranasal inoculation with HSV-1.
- Mice received oral or intraperitoneal (i.p.) administration of acyclovir (ACV), bromovinyldeoxyuridine (BVdU), or dihydroxypropoxymethylguanine (DHPG).
- Therapeutic efficacy was assessed by mortality rates, viral load, antigen detection, and viral DNA presence in neural tissues via Southern blotting.
Main Results:
- Oral ACV was effective preventatively but less so once infection was established.
- Intraperitoneal ACV showed reduced efficacy compared to DHPG.
- DHPG demonstrated superior effectiveness, rapidly eradicating infectious virus, antigens, and DNA from the brain by day 10.
Conclusions:
- Dihydroxypropoxymethylguanine (DHPG) is a highly effective treatment for established herpes encephalitis.
- DHPG exhibits superior antiviral activity in the central nervous system compared to ACV and BVdU.
- Early intervention with antivirals is crucial, but DHPG offers a promising therapeutic option for established infections.