Neurosurgery Department, General University Hospital Alicante, Spain
Minocycline is primarily known as an antibiotic and is often used for treating bacterial infections, acne, and some inflammatory conditions. However, its potential use in hydrocephalus treatment is a more novel application and is related to its properties beyond antimicrobial activity, including its anti-inflammatory and neuroprotective effects.
1. Anti-Inflammatory Properties: Minocycline has been shown to have anti-inflammatory effects, which may be beneficial in conditions where inflammation contributes to disease progression. In hydrocephalus, especially when induced by hemorrhage or infection, inflammation can play a significant role.
2. Neuroprotection: Minocycline has neuroprotective properties that could help in reducing neuronal damage and improving outcomes in neurological conditions. This may be beneficial in managing complications associated with hydrocephalus.
3. Research Findings:
4. Mechanism: Minocycline might influence hydrocephalus through:
5. Clinical Implications: While animal studies show promise, further research, including clinical trials, is needed to evaluate minocycline's efficacy and safety in treating hydrocephalus in humans. The drug would need to be tested for its ability to improve symptoms, reduce CSF accumulation, and assess any potential side effects in the context of hydrocephalus treatment.
In summary, minocycline’s potential use in hydrocephalus is based on its anti-inflammatory and neuroprotective properties, but its application in this context is still under investigation.
Currently, several appropriate animal models are available to mimic the clinical outcomes of Germinal Matrix Hemorrhage in human patients. In the long run, hemorrhagic strokes are the research target. Previously, they found that minocycline was efficient in alleviating GMH-induced brain edema and posthemorrhagic hydrocephalus (PHH) in rats, which may be closely related to the activation of cannabinoid receptor 2 (CB2R). However, how the two molecules correlate and the underlined molecular pathway remain unknown. To extensively understand current experimental GMH treatment, a literature review critically evaluates existing therapeutic strategies, potential treatments, and potentially involved molecular mechanisms. Each strategy has its advantages and disadvantages. Some of the mechanisms are still controversial, requiring an increasing number of animal experiments before the therapeutic strategy would be widely accepted 1)
A study examined using T2* magnetic resonance imaging (MRI) to detect periventricular iron deposition after IVH and investigated the effects of minocycline on hydrocephalus in an aged rat IVH model. It had three parts. In part 1, male aged rats received a 200 μl injection of saline or autologous blood into the lateral ventricle and were euthanized at day 14. In parts 2 and 3, aged IVH rats were treated with vehicle or minocycline and euthanized at day 7 or 14. Rats underwent MRI to quantify hydrocephalus and iron deposition followed by brain histology and immunohistochemistry. Periventricular iron overload was found after IVH using T2* MRI and confirmed by histology. IVH also caused ventricular wall damage and increased the number of CD68(+) choroid plexus epiplexus cells. Minocycline administration reduced iron deposition and ventricular volume at days 7 and 14 after IVH, as well as ventricle wall damage and epiplexus cell activation. In summary, IVH-induced hydrocephalus is associated with periventricular iron deposition, ependymal damage, and choroid plexus epiplexus cell activation in aged rats. Minocycline attenuated those effects and might be a potential posthemorrhagic hydrocephalus treatment in the elderly 2).
Evidence indicates that erythrocyte-derived iron and inflammation both play a role in intraventricular hemorrhage-induced brain injury including hydrocephalus. Many immune-associated cells, primarily stromal macrophages, reside at the choroid plexus where they are involved in inflammatory responses and antigen presentation. However, whether intraventricular iron impacts those stromal cells is unknown. Bian et al. evaluated the relationship between choroid plexus stromal macrophages and iron-induced hydrocephalus in rats and the impact of minocycline and clodronate liposomes on those changes. Aged (18-month-old) and young (3-month-old) male Fischer 344 rats were used to study choroid plexus stromal macrophages. Rats underwent intraventricular iron injection to induce hydrocephalus and were treated with either minocycline, a microglia/macrophage inhibitor, or clodronate liposomes, a macrophage-depleting agent. Ventricular volume was measured using magnetic resonance imaging, and stromal macrophages were quantified by immunofluorescence staining. They found that stromal macrophages accounted for about 10% of the total choroid plexus cells with more in aged rats. In both aged and young rats, intraventricular iron injection resulted in hydrocephalus and increased stromal macrophage number. Minocycline or clodronate liposomes ameliorated iron-induced hydrocephalus and the increase in stromal macrophages. In conclusion, stromal macrophages account for ~10% of all choroid plexus cells, with more in aged rats. Treatments targeting macrophages (minocycline and clodronate liposomes) are associated with reduced iron-induced hydrocephalus 3)
A study aimed to determine sex differences in hydrocephalus development and to examine the effect of minocycline administration after hydrocephalus onset. Male and female Wistar-Kyoto rats (WKYs) and SHRs underwent magnetic resonance imaging at weeks 7 and 9 to determine ventricular volume. Choroid plexus epiplexus cell activation, cognitive deficits, white matter atrophy, and hippocampal neuronal loss were examined at week 9. In the second phase of the experiment, male SHRs (7 weeks old) were treated with either saline or minocycline (20 mg/kg) for 14 days, and similar radiologic, histologic, and behavior tests were performed. Hydrocephalus was present at week 7 and increased at week 9 in both male and female SHRs, which was associated with greater epiplexus cell activation than WKYs. Male SHRs had greater ventricular volume and epiplexus cell activation compared to female SHRs. Minocycline administration improved cognitive function, white matter atrophy, and hippocampal neuronal cell loss. In conclusion, while both male and female SHRs developed hydrocephalus and epiplexus cell activation by week 9, it was more severe in males. Delayed minocycline treatment alleviated hydrocephalus, epiplexus macrophage activation, brain pathology, and cognitive impairment in male SHRs 4).
Tang et al. investigated the role of the C3/C3aR pathway in microglia and astrocyte interactions and whether C3/C3aR-targeted inhibition could alleviate PHH following GMH-IVH. A total of 152 Sprague-Dawley rats at postnatal day seven (P7) were enrolled in the study, and collagenase VII was used to induce GMH-IVH. Minocycline (45 mg/kg) was administered to inhibit microglial activation. Complement C3a peptide and C3aR antagonist (SB 290157, 10 mg/kg) were used to regulate the C3/C3aR pathway. As a result, the data demonstrated that periventricular C3aR+/Iba-1+ microglia and C3+/GFAP+ astrocytes were significantly increased in GMH-IVH pups at 28 days after surgery. Intranasal C3a peptide upregulated C3aR expression in microglia. Inhibition of microglia by minocycline decreased both C3+/GFAP+ astrocytes and the colocalization volume of Iba-1 and GFAP. In addition, intraperitoneally injected C3aRA alleviated the periventricular colocalization volume of microglia and astrocytes. Compared with vehicle-treated pups, the protein levels of IL-1β, IL-6, and TNF-α in cerebral spinal fluid and brain tissue at 28 days following GMH-IVH were reduced in C3aRA-treated pups. Moreover, hydrocephalus was alleviated, and long-term cognitive ability were improved in the C3aRA-treated group. Our data presented simultaneous periventricular astrogliosis and microgliosis of pups following GMH-IVH and proved their potential interaction through the C3/C3aR pathway, indicating C3aRA as a potential pharmacological treatment of PHH in neonates 5)
The ventricular dilatation was evaluated by MRI at 1-week post-drug treatment, while GFAP and Iba-1 were detected by RT-PCR, Immunohistochemistry, and Western blot. The expression of GFAP and Iba-1 was significantly higher in the hydrocephalic group compared with the saline control group (p < 0.05). Minocycline treatment of hydrocephalic animals reduced the expression of GFAP and Iba-1 significantly (p < 0.05). Likewise, the severity of ventricular dilatation is lower in minocycline-treated hydrocephalic animals compared with the no-minocycline group (p < 0.05).
Minocycline treatment is effective in reducing gliosis and delaying the development of hydrocephalus with the prospective to be the auxiliary therapeutic method of hydrocephalus 6)