The effectiveness of current treatments for mitochondrial disease varies from patient to patient and depends on the type of affected cells and the severity of their disease. In general, those with milder mitochondrial disorders will experience more success with treatment than those with severe mitochondrial disorders. Some patients can experience symptom relief and slowed progression of mitochondrial disease with treatment programs tailored expertly to their specific set of symptoms. For other patients, however, personal treatment plans that should be effective do not result in benefits or improvement.
The success of treatment for mitochondrial disease also happens on a case-by-case basis. Some patients will see immediate benefits from therapy, while others may not experience benefits until several months into treatment programs. For others, treatment for mitochondrial disease may effectively slow the progression of the disease on a cellular level without displaying any noticeable relief of symptoms for the patient.
While it is not definite mitochondrial dysfunction is the cause of other disorders, mitochondrial dysfunction or failure is evident in these diseases.
Current Treatments for Mitochondrial Disease
For those navigating the confusing ups and downs of mitochondrial disease, medical marijuana can help. Cannabis offers relief from many symptoms of mitochondrial diseases, as well as conditions that can result from a mitochondrial disorder. If you are suffering from a mitochondrial disease, medical marijuana may be the natural treatment you have been looking for.
Medical marijuana for mitochondrial disease may help maintain the balance of autophagy and apoptosis in cells in varied ways. THC in smaller doses can increase mitochondrial activity by interacting with the mitochondrial membrane to promote the creation of ATP. This process also aids in cell regeneration by triggering autophagy that repairs damaged cell parts. Higher doses of THC can decrease the activity of mitochondria by binding to CB1 receptors to decrease mitochondrial activity and thus decrease oxidative stress. Cannabinoids may also suppress neurodegeneration to slow the aging process and slow the onset of dementia.
Because mitochondrial diseases can vary so widely, patients should consult a physician before beginning any treatments, including altering their diet.
Mitochondrial disease also links to a wide range of other diseases. Mitochondria play a role in proper neuron functioning, as neurons require a high amount of energy to function properly. Mitochondrial failure in neurons can lead to neurodegenerative disorders, such as Alzheimer’s and other dementias. Mitochondrial dysfunction is also evident in many other ailments, including:
Since an antioxidant capacity has been widely reported for CBD (Hampson et al., 1998; Chen and Buck, 2000), its neuroprotective properties were subsequently compared with the protective capabilities of the free radical scavenger butylated hydroxytoluene (BHT). Interestingly, coapplication of FCCP with BHT (at 3 and 10 μ m ; n values = 11 and 12, respectively) conferred no significant protection (p values >0.05), yet joint application of CBD (1 μ m ) applied with the higher concentration of BHT (10 μ m ) provided a complete prevention of FCCP’s toxic effects [100 ± 7% protection (n = 12), p < 0.001 compared with FCCP controls], significantly more potent than CBD alone (p < 0.001) ( Fig. 9 B). The superadditive nature of this protection strongly suggests independent but synergistic modes of action. Overall, our data suggest that CBD directly acts on mitochondria, and this action offers protection against toxins that directly target mitochondria.
The mitochondrial and cytosolic Ca 2+ compartments were visualized simultaneously by preloading cultures with the mitochondrion-specific Ca 2+ sensor Rhod-FF, AM (Invitrogen). Culture dishes were incubated with Rhod-FF, AM (5 μ m , in standard HBS) for 15 min on the day before experimentation to allow compartmentalization of the marker (specificity of this marker was confirmed by the abolition of compartmentalization by FCCP application) (see Fig. 4 Ci,Cii). HBS was replaced with fresh Neurobasal medium and returned to the incubator overnight. The following day, cells were loaded with fura-2 AM as described above. Dual imaging was performed with alternating wavelengths relevant to Rhod-FF (excitation: 550 nm; emission: 580 nm) and fura-2 AM (as above) delivered at intervals of 3 s. Both images were background subtracted, and separate graphs were plotted on-line (see Fig. 4 ). For off-line analysis of mitochondrial responses, data were imported into the Volocity analysis program (version 4.02, Improvision). Areas of most intense Rhod-FF mitochondrial fluorescence within a single neuron were allocated ROIs.
Two fundamental determinants of neuronal survival and viability under pathological conditions are Ca 2+ homeostasis and metabolic activity, both reliant on mitochondrial function. Neurons have a particularly high energy demand and correspondingly high metabolic activity, alongside large fluctuations in [Ca 2+ ]i; thus, mitochondria play a particularly important role in this cell type. Even subtle mitochondrial deficits can have deleterious effects that can ultimately result in degenerative processes (for review, see Kajta, 2004). Energy deficiencies are also associated with aging (Bowling et al., 1993) (for review, see Wiesner et al., 2006) and age-related disorders, e.g., Alzheimer’s disease (de la Monte and Wands, 2006), indicating a correlation with mitochondrial dysfunction, as also recently suggested by a corresponding treatment success in Alzheimer’s patients (Doody et al., 2008). Mitochondria are preferentially located in areas of highest [Ca 2+ ]i adjacent to the endoplasmic reticulum, essential for the functional coupling of these two organelles (Robb-Gaspers et al., 1998; Szabadkai et al., 2003; Saris and Carafoli, 2005). Moreover, mitochondria determine cellular survival by generation of reactive oxygen species (Lafon-Cazal et al., 1993) and apoptotic factors (Hong et al., 2004). This process involves an increased permeability of mitochondrial membranes [including opening of the mitochondrial permeability transition pore (mPTP) (Hunter et al., 1976)]. Therefore, identification of agents that can restore normal mitochondrial function is highly desirable.
Protection by CBD against mitochondrial toxins
Hippocampal cultures were preincubated with CBD for 1 h before coapplication of CBD with mitochondrion-acting toxins overnight, following which cell death was quantified using a Live-Dead staining kit (Sigma) (modified from our previous publications) (Platt et al., 2007). Briefly, 10 μl of solution A and 4 μl of solution B were diluted in 5 ml of HBS (at room temperature). Each dish was washed in HBS three times and 500 μl of the staining solution added and incubated for 20 min (in the dark, at room temperature). After a further wash with HBS, live images were capture in HBS with a 40× phase-contrast water-immersion objective [brightfield, FITC (live cells) and rhodamine filters (dead cells)] using an Axioskop 2 plus microscope (Carl Zeiss) fitted with an AxioCam HRc camera, with AxioVision software (version 3.1). Three images were taken from each dish and each experiment performed on at least two dishes from three different cultures.
Each treatment and relevant vehicle controls were run in six samples (wells) per experiment and repeated at least twice, viability was compared using the nontoxic cell viability marker Alamar Blue (Serotec). This marker was made up as a 10% solution in MEM and applied to all wells (following the removal of treatment medium) for 2 h at 37°C, 5% CO2. The plates were then run in a plate reader (either Victor 2 1420, Wallac, Perkin-Elmer or Synergy HT, Bio-Tek) and the fluorescence (excitation: 530 nm and emission: 590 nm) measured.
Effects of ER- and mitochondrion-acting drugs on CBD responses. A, B, The role of mitochondria in CBD responses were confirmed in neurons (A) and glia (B). The uncoupler FCCP prevented neuronal CBD response and largely reduce glial responses while blockade of IP3 and ryanodine receptors [by 2-APB and dantrolene (Dant.), respectively] did not significantly alter CBD responses in neurons, a sample trace of which is also shown (C). In the presence of CGP 37157 (CGP), but not in the presence of the mPTP inhibitor cyclosporin A (CsA), CBD responses were also blocked in normal and high-excitability HBS; CBD responses under high-excitability conditions no longer differed from standard HBS responses. Data are presented as %ΔF/F + SEM; n.s., not statistically significant; **p < 0.01, ***p < 0.001.
The plant Cannabis sativa has for many centuries been reputed to possess therapeutically relevant properties. Its most widely studied and characterized component, Δ 9 -tetrahydrocannabinol (THC), is one of 60+ compounds from Cannabis sativa, collectively known as phytocannabinoids. However, THC may have a limited usefulness due to psychoactivity, dependence, and tolerance (Sim-Selley and Martin, 2002); therefore, attention has turned to some of the nonpsychoactive phytocannabinoids, most notably cannabidiol (CBD). CBD has little agonistic activity at the known cannabinoid receptors (CB1 and CB2) (Pertwee, 2004), and may possess therapeutic potential, e.g., anti-epileptic (Cunha et al., 1980), anxiolytic (Guimarães et al., 1994), anti-inflammatory (Carrier et al., 2006), and even anti-psychotic properties (Leweke et al., 2000) [for review, see Pertwee (2004) and Drysdale and Platt (2003)]. In addition, CBD has shown neuroprotection in a range of in vivo (Lastres-Becker et al., 2005) and in vitro models (Esposito et al., 2006), some in association with a reduction in [Ca 2+ ]i (Iuvone et al., 2004).